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(Circulation. 1997;96:4065-4082.)
© 1997 American Heart Association, Inc.

Articles

Extracellular Matrix Remodeling in Heart Failure

A Role for De Novo Angiotensin II Generation

Karl T. Weber, MD

From the Division of Cardiology, Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia.

Correspondence to Karl T. Weber, MD, Division of Cardiology, MA432 Medical Sciences Building, University of Missouri Health Sciences Center, Columbia, MO 65212.

Key Words: angiotensin • collagen • diastole • heart failure • remodeling

	Introduction

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
Heart failure is a major health problem worldwide. In the United States, it represents the number one hospital discharge diagnosis among elderly persons each year. It appears most commonly in patients with previous MI.^1,2 The chronically failing heart of ischemic origin is characterized by iterations in tissue structure, particularly fibrous tissue formation, that appear in infarcted and noninfarcted myocardium of both right and left ventricles.^3,4 In other words, fibrosis appears at the site of MI as well as remote from it. Fibrosis remote from the infarct site is considered "the major cause of ventricular remodeling" in ischemic cardiomyopathy.⁴ Such an adverse accumulation of extracellular matrix initially raises myocardial stiffness; its continued accumulation further increases stiffness and impairs contractile behavior.^5–10 Elucidating cellular and molecular mechanisms responsible for accumulation of extracellular matrix is essential to designing cardioprotective and reparative strategies that could prevent or regress fibrosis, respectively, after infarction.^11,12

ACE inhibition has proved effective in reducing mortal and morbid events, improving symptomatic status, and attenuating the progressive nature of cardiac failure in symptomatic patients with ventricular diastolic and/or systolic dysfunction in whom activation of the circulating RAAS is present.^1,13,14 ACE inhibitor–mediated reductions in circulating Ang II and aldosterone no doubt contribute to this salutary response. This would include an attenuation of well-recognized endocrine properties of these hormones, such as altered sodium homeostasis and vascular tonicity, and their adverse influence on matrix structure of atria and ventricles.^15–20 Collectively, these adverse responses to RAAS effector hormones contribute to the progressive nature of chronic cardiac failure, which includes recurring bouts of symptomatic failure^1,2,21 and reentrant arrhythmias originating in either atria or ventricles.^22,23

ACEIs have also proved effective in asymptomatic patients with equivalent levels of ventricular systolic dysfunction but in whom chronic RAAS activation is not present.^2,24,25 Attention has therefore focused on the importance of Ang II generated de novo within the infarcted heart.²⁶ ACE, a membrane-bound ectoenzyme found on various cells, is central to Ang II generation within an organ.²⁷ Because ACE mRNA expression and activity are each increased in tissue homogenates taken from either the infarcted failing ventricle or the hypertrophied, hypertensive ventricle,^28–32 it has been proposed that these responses are a consequence of cardiac myocyte hypertrophy and/or increased systolic wall stress.^31,32 Increased ACE activity, however, is most specifically localized to sites of fibrosis, such as ventricular aneurysm in the infarcted heart,²⁹ a finding reinforced by autoradiographic localization of high-density ACE binding at the site of MI.³³ Marked ACE binding is also seen at sites of repair remote from the infarct (eg, noninfarcted right ventricle) and sites independent of infarction (eg, fibrosed visceral pericardium),³³ where ACE activity (Ang I substrate conversion) is present.^30,34 Hence, increased expression of ACE transcript and activity do not appear to be related to hemodynamic factors or to cardiac myocyte hypertrophy. Cells expressing ACE at sites of repair include a phenotypically transformed fibroblast-like cell, the myoFb, because it expresses -SMA and is contractile.^35,36

Locally produced Ang II has autocrine and paracrine properties that influence the behavior of constitutive cell populations of the myocardium via Ang II receptor binding. Various paradigms have been suggested, including Ang II–mediated cardiac myocyte hypertrophy³⁷ and apoptosis,^38,39 regulation of microvascular blood flow at sites of injury,⁴⁰ and the process of tissue repair itself.⁴¹

This report addresses various lines of evidence that implicate Ang II, generated de novo at sites of high collagen turnover, in regulating connective tissue formation. This applies to normal (eg, heart valve leaflets) and pathological sites of tissue repair. On the basis of these collective findings, it is suggested that Ang II, produced de novo at sites of injury in the heart and pericardium, is integral to their repair. Let's set the stage for this Bench to Bedside review with a fictional vignette.

	Clinical Vignette: Bee Stings and Other Things

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
This warm Tuesday evening in July found internist Mindy Carson at her modest yet comfortable office in central Missouri. Standing by an open window with arms folded, her head resting on the window frame, she pensively gazed at the familiar sight of grazing cattle on neighboring farmland. As was her custom, Mindy reflected on the day's prior events: morning rounds at the hospital, an afternoon of office-based patients. A year had passed since she began her practice; it had proved gratifying and intellectually challenging. Just before closing today, for example, her patient Joseph McKenzie had brought sons Jim and John, ages 10 and 12 years, to the office. John's entire right hand had become swollen, red, and painful after multiple honeybee stings. Jim, more fortunate, had only a single sting with a localized wheal and flare. Antihistamine and topical care for John, comfort and assurance for both. Mindy also examined Joseph's hand. A carpenter by trade, years of hammering and sawing had caused thickened palmar fascia of his right hand to contract, with a consequent retraction of the fourth and fifth digits toward the palm (Dupuytren's contracture). As the McKenzies were leaving, she reminded Joseph that surgery would be needed if his hand was to remain functional and he gainfully employed.

Mindy sat at her desk to ponder Joseph's fibrocontractive disorder, her mind struggling to understand its pathophysiological basis. She began drumming the eraser end of her pencil on the desk to an imaginary rhythm. Like a Gene Krupa drum solo from the swing era of jazz, her rendition built in intensity and pace. "Strange," she thought, "a drumhead's stretched membrane of cowhide does not contract. Why would Joseph's palmar fascia?" For that matter, why would scarred rheumatic mitral leaflets retract and become incompetent? There were no contractile proteins in fibrous tissue to mediate such responses. Or were there? She quickly turned to her personal computer for a search of the medical literature in hopes of unraveling the puzzle. As an internist—integrator of basic and clinical sciences—she reminded herself that tissue, defined as a substance of an organ, consists of intercellular material, in this case fibrillar collagen, and cells. "That's it," she exclaimed, "it must be the cells!" Bursting with ideas, her mind racing, she wondered whether such circumstances could also explain Mrs Carver's problem.

Mindy had seen Ruth Carver in the ICU earlier in the day. This 67-year-old woman had had an uneventful anterior MI 6 months earlier, without clinical evidence of ventricular dysfunction or arrhythmia. After hospital discharge, she noted the gradual appearance of dyspnea with moderate levels of exertion, particularly evident over the past several months. Last evening, paramedics brought Ruth to the ER because of severe breathlessness. There, Mindy found her tachypneic and orthopneic: blood pressure 180/100 and an irregular heart rate of 140 bpm, with a pulse deficit of 50 bpm. She denied chest pain. Neck veins were not distended, apical impulse not displaced; no S₃ gallop or murmur; bibasilar crackles without pleural effusion, hepatomegaly, or pitting ankle edema. The ECG showed atrial fibrillation without acute MI or ischemia. Serum creatine kinase MB fraction likewise did not support MI. Mindy's diagnosis: acute pulmonary edema. She chose electrical cardioversion to restore sinus rhythm and intravenous furosemide to induce a diuresis and clear pulmonary congestion. Thereafter, Mrs Carver's blood pressure returned to its usual normotensive value and she was breathing more comfortably; she was hospitalized for further observation.

Mindy was gratified this morning when she noted Ruth's continued recovery. But she was curious. The appearance of atrial fibrillation, with rapid ventricular rate and lost atrial contraction, was inextricably linked to her pulmonary edema. Other patients Mindy followed, without structural heart disease, had tolerated similar episodes of atrial fibrillation without such sequelae. Why had atrial fibrillation precipitated pulmonary edema in Ruth? DD with acute pulmonary venous hypertension seemed most likely. Mindy obtained an echocardiogram from the health center's outreach program later in the day: ejection fraction, 45%; DD as evidenced by an abnormal E/A wave ratio; and absent mitral valve incompetence or ventricular aneurysm. With her clinical impression confirmed, she wondered: What leads to DD after infarction? Mindy pondered whether the hands of the McKenzie family provided clues.

Mindy prescribed an ACEI and in subsequent weeks was delighted when Ruth no longer experienced dyspnea on exertion. Her patient's annoying cough would prompt a switch to an AT₁ receptor antagonist. A repeat echocardiogram, months later, would demonstrate improved DD and an ejection fraction of 52%.

	Ventricular Dysfunction and the Clinical Spectrum of Heart Failure

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
The severity of LVD, which accompanies acute MI, whether expressed in clinical or hemodynamic terms, is an important determinant of short-term survival.^42–44 Chronic LVD, seen most frequently in patients with previous MI, is likewise an important prognostic factor.^1,2,45–47 A chronic impairment in ventricular systolic or diastolic mechanics of the right and/or left ventricles^48–50 will compromise cardiac output reserve to the physiological stress of exercise.^51,52 This leads to reduced lactate threshold, increased CO₂ production and minute ventilation relative to work performed,⁵³ and associated symptoms of exertional breathlessness and fatigue.⁵⁴

LVD per se does not account for a decompensated clinical state of symptomatic cardiac failure.^1,2 This has been clearly underscored by the Studies of Left Ventricular Dysfunction (SOLVD) trial, in which an ejection fraction 35% as entrance criterion was satisfied in both symptomatic patients with decompensated failure (treatment arm) and asymptomatic patients with compensated failure (prevention arm).^1,2 Decompensated failure is manifested by signs and symptoms of extravascular volume expansion (eg, pleural effusion, pitting edema). It occurs when renal perfusion is significantly impaired and accompanied by marked proximal and distal tubular sodium resorption. This sodium-avid state is mediated via a chronic activation of the circulating RAAS.^55–57 Accompanying elevations in circulating Ang II and aldosterone are inappropriate as contrasts to states of sodium deprivation or intravascular volume depletion. Compensated failure, in which patients are asymptomatic, exists when the circulating RAAS has not been activated and as a result renal sodium excretion remains normal.

Ventricular diastolic and systolic dysfunction is based on an adverse structural remodeling of the myocardium (see Fig 1). This includes the population of cardiac myocytes, in which, over time, hypertrophy, necrosis, and apoptosis alter myocyte mass, and a progressive accumulation of fibrous tissue. Fibrosis appears in morphologically distinct forms. This includes a reactive form, expressed as a perivascular/interstitial fibrosis, which appears in the absence of myocyte necrosis, and a reparative fibrosis or microscopic scars that replace necrotic myocytes.¹⁵ Initially, fibrous tissue will adversely influence tissue stiffness and diastolic mechanics.^{5,6,9,58–62} This includes recruiting the length-dependent property of cardiac muscle (Frank-Starling mechanism) during volume loading,^8,63,64 such as occurs with increased venous return attendant on incremental isotonic exercise. A continued accumulation of matrix further impairs diastolic stiffness and now compromises systolic mechanics, including tissue contractility.^6,65 Ultimately, renal perfusion falters. Decompensated failure is associated with increased mRNA expression of matrix proteins (eg, types I and III collagens) and accumulation of corresponding proteins expressed as cardiac fibrosis.^66–68

View larger version (31K): [in this window] [in a new window]   Figure 1. Overview of interrelationship between structural remodeling of myocardium and ventricular function in normal and failing hearts. Included are schematic responses in cardiac myocyte mass (hypertrophy, necrosis, apoptosis); collagen concentration (reactive and reparative fibrosis); diastolic stiffness; myocardial contractility; and activation of circulating RAAS, which alters renal sodium excretion to determine whether failing heart is associated with (decompensated) or without (compensated) symptoms and signs of heart failure. See text for discussion.

	Cardiac Remodeling and the Infarcted Heart

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
Fibrosis and Ischemic Cardiomyopathy
In Robbins' Pathophysiologic Basis of Disease, Cotran et al³ indicate that major histological findings in ischemic cardiomyopathy include "a diffuse myocardial atrophy... of myocytes; a diffuse, mainly perivascular, interstitial fibrosis; patchy (under 1 cm) foci of fibrous tissue; myocytolysis of single cells or clusters of cells; and in some instances large healed scars of previous acute infarctions." Using the explanted failing human heart of ischemic origin, Beltrami et al⁴ extend these observations, noting the presence of multiple foci of replacement fibrosis in combination with interstitial fibrosis in both right and left ventricular myocardium, and such fibrosis, remote from the infarct, accounts for more than two thirds of fibrous tissue found in the cardiomyopathic heart of ischemic origin, whereas the infarct scar constitutes one third. They conclude that "while the cardiomyopathic process may be initiated by myocyte loss after MI, its evolution appears to be controlled by events occurring in remote noninfarcted myocardium of both ventricles." Factors responsible for the accumulation of collagen in the infarcted and noninfarcted myocardium draw attention to the fibrogenic component of tissue repair.

Overview of Tissue Repair
Healing is a property common to all vascularized tissues. A reparative process is initiated after cardiac myocyte necrosis. This initially depends on inflammatory cells, such as monocytes and macrophages, that invade the site of injury. Macrophages are activated and thereafter generate peptides integral to repair. Fibroblasts are subsequently attracted to the site of injury, where they convert to myoFbs. Through a complex series of molecular events that includes expression of immediate early response genes (eg, c-fos, c-jun, and egr-1) and activation of multiple second messenger systems, which act synergistically to induce mitosis, these cells proliferate and lay down fibrillar collagen that replaces lost myocytes.^69–72 Cells involved in repair are bathed by tissue fluid whose composition regulates their phenotype and behavior. A diverse array of soluble regulatory signals, whose biological properties are expressed via receptor-ligand binding, gain access to tissue fluid of the interstitial space from necrotic myocytes, leukocytes, macrophages, and myoFbs. Monitoring lymphatic^73–75 or venous drainage^76,77 of the injured heart provides insights to the nature of these signals and their broad-ranging functions that regulate cell migration and differentiation, cell-cell interactions, and gene expression.⁷⁸

Fibrous tissue formation is essential to preserving structural integrity of the infarcted myocardium at the site of myocyte loss. Provided that the degree of parenchymal damage is minor, regulatory signals are confined to the site of necrosis. This resembles the local release of histamine and the subsequent wheal-and-flare response that accompanies a single bee sting. Multiple bee stings evoke a large histamine response widely dispersed within tissue fluid, which then promotes diffuse organ swelling. Such is the case with a large transmural MI, in which signals originating at the site of injury are widely dispersed within the common interstitial space of both ventricles to elicit a fibrogenic response in the noninfarcted portion of the injured ventricle and the noninfarcted ventricle.^33,64,79,80 Signals involved in repair after MI, however, are confined to the heart; systemic organs are not involved. When fibrogenic signals gain access to the circulation (see below) and are not neutralized, systemic organs will be involved in an unwanted accumulation of stroma—a wound-healing response gone awry.

Collagen Turnover At and Remote From Infarction
Collagen turnover has been studied at the site of infarction and at remote sites after ligation of the rat left coronary artery. At the infarct site, collagen degradation, particularly its neutral salt and acid-soluble fractions,⁸¹ exceeds synthesis during the very early phase of repair. MMPs reside in the myocardium in latent form. When activated, MMP-1 (or interstitial collagenase) degrades fibrillar collagen into 1/4-length and 3/4-length fragments; gelatinases (MMP-2 and MMP-9) degrade these smaller fragments. An increase in collagenase activity appears at the infarct site on day 2, peaks by day 7, and declines thereafter, together with increased gelatinase activity.⁸² An increase in collagenase (MMP-1) mRNA expression appears only at day 7 in the infarcted ventricle, replacing the consumed latent pool. TIMPs neutralize collagenolytic activity. Transcription of TIMP mRNA at the infarct site peaks on day 2 and declines slowly over the course of 14 days. Events related to collagen degradation are not seen remote from the MI. Fibroblast-like cells, not inflammatory or endothelial cells, are responsible for the transcription of MMP-1 and TIMP mRNAs.⁸²

A fibrogenic component of healing, including an initial expression of fibronectin mRNA,⁸³ follows early collagen degradation. By Northern blot and in situ hybridization analyses, type III procollagen mRNA at the infarct site is increased by day 2 post-MI, reaching a peak by day 21 and declining thereafter.⁸⁴ Type I procollagen mRNA increases at day 4 and remains elevated at week 4 (see Fig 2A) and even until day 90 at the site of infarction,⁸⁴ suggesting that collagen synthesis is an ongoing process in keeping with the persistence of myoFbs at this site.^85,86 To a lesser extent than seen at the site of injury, but still evident, is the rise in procollagen mRNA remote from the infarct.^84,87 Procollagen I and III mRNAs are increased in the right ventricle and interventricular septum on days 4 and 7, respectively.⁸⁴ In the septum, closest to the infarct, type I procollagen mRNA remains elevated until day 28 (see Fig 2A) but in the right ventricle only until day 7. Expression of type I collagen mRNA is also increased in the fibrosed visceral pericardium at week 4 post-MI (see Fig 2A). These responses, involving myoFbs at the infarct and remote sites (see below),^84,86 are associated with increased expression of TGF-ß₁ mRNA.⁸⁷

View larger version (123K): [in this window] [in a new window]   Figure 2. Tissue repair in infarcted rat heart induced by permanent left coronary artery ligation. Data are presented for week 4 postinfarction (MI). A, In situ hybridization for type I collagen mRNA expression. Increased expression of type I collagen mRNA (yellow and red) is seen at site of transmural left ventricular MI. Same is true at remote sites that include interventricular septum (S) and right ventricle (RV). This involves endocardial fibrosis (EF) of S, a perivascular fibrosis and microscopic scarring of S and RV, and fibrosis of visceral pericardium (PF). B, Picrosirius red collagen-specific staining demonstrates fibrillar collagen accumulation at site of MI, EF, perivascular fibrosis of intramural vessels (CA), and PF. C, Autoradiographic detection of ACE-binding density. High-density ACE binding (white, red, and yellow) is seen at site of MI, EF, and PF. D, Autoradiographic detection of Ang IIR binding. High-density Ang IIR binding is anatomically coincident with high-density ACE binding and sites of type I collagen mRNA expression and fibrous tissue formation. C and D reproduced with permission from References 33 and 134.

By picrosirius red staining, collagen fibers are morphologically evident at the infarct site by day 7, and an organized assembly of fibers in the form of scar tissue becomes evident by day 14 and continues to accumulate for many weeks (see Fig 2B).^33,88 Hydroxyproline concentration at the site of scarring increases progressively from week 1 to week 6, as does collagen crosslinking.^89–91 A thinning of infarct scar is evident by week 8. Remote from the infarct, including viable left ventricle, interventricular septum, and right ventricle, fibrillar collagen appears by day 14, continues to accumulate for weeks (see Fig 2B), and is associated with increased pepsin-insoluble collagen.^{4,62,64,79,80,91}

MyoFbs and Repair
MyoFbs are central to fibrogenesis at sites of repair. Fibroblasts have an extensive clonal heterogeneity, and these phenotypically transformed fibroblast-like cells have considerable diversity.^35,92 This includes their synthesis of structural proteins and expression of receptors for Ang II, TGF-ß₁, and endothelins, which permit their response to these regulatory molecules. In addition, myoFbs express -SMA and are contractile, and, relevant to this report, they govern fibrogenesis in the heart,^86,93,94 pericardium, and systemic organs secondary to diverse forms of injury.³⁵ These -SMA–positive cells (see Fig 3A) appear at sites of injury within days of cardiac myocyte necrosis^33,93–95 and are responsible for increased expression of genes encoding for fibrillar type I/III procollagens and their synthesis.^33,96,97 MyoFbs arise from interstitial fibroblasts and/or pericytes, not vascular smooth muscle cells or cardiac myocytes.^35,36 MyoFb contraction governs matrix remodeling, including scar thinning.⁹⁸ The contractile behavior of fibrous tissue is related to myoFbs having -SMA and their cell-cell (desmosome and gap junction types) and cell-matrix (fibronexus, a transmembrane association between fibronectin fibers and actin microfilaments) connections. Their influence on DD of the infarcted ventricle and abnormal tissue stiffness at remote sites will be addressed later in this report.

View larger version (156K): [in this window] [in a new window]   Figure 3. Cellular responses seen in serial sections of infarcted rat heart postinfarction. A, Immunolabeling for -SMA. At week 2, myofibroblasts expressing -SMA have surrounded site of necrosis (Nec) (x400). B, Myofibroblasts (arrowhead) and macrophages express ACE, as demonstrated by monoclonal antibody labeling, at site of Nec 2 weeks post-MI (x540). C, Intense -SMA labeling is also seen at site of pericardial fibrosis (PF) 2 weeks post-MI (x400), where they express ACE (D) (x540). E, -SMA labeling at infarct site, 4 weeks post-MI, identifies vascular smooth muscle cells found in two intramyocardial coronary arteries (V) and myofibroblasts (MF) found at site of necrosis (center) and endocardial fibrosis (top) (x120). F, Autoradiography demonstrates that myofibroblasts express high-density Ang IIR binding at site of infarction 4 weeks post-MI. Same vessels (V) as shown in E demonstrate low-density Ang IIR binding (x120). Reproduced with permission from References 86 and 148.

Signals that determine the appearance of the myoFb phenotype are not entirely certain. TGF-ß₁ is contributory. Subcutaneous administration of TGF-ß₁ leads to the appearance of myoFbs within granulation tissue that forms, which is not the case for platelet-derived growth factor or tumor necrosis factor-.⁹⁹ Cultured adult skin fibroblasts undergo a phenotype switch and express -SMA when incubated with TGF-ß₁.⁹⁹ The appearance of TGF-ß₁ at sites of injury is most likely related to necrotic myocytes,^100,101 activated macrophages,¹⁰² and myoFbs themselves.¹⁰³

A fibrillar fibrin-fibronectin scaffolding forms soon after tissue injury and is the precursor to granulation tissue formation and the attachment of myoFbs via a fibronexus.¹⁰⁴ MyoFbs subsequently elaborate type III and then type I collagens, the major fibrillar collagens that constitute fibrous tissue.^105–107 At pathological sites of tissue repair in the heart, including the site of MI, in situ hybridization has shown that myoFbs express types I and III collagen transcripts.^33,84 MyoFbs elaborate and metabolize various substances that regulate their turnover of collagen and govern fibrous tissue contraction in an autocrine manner (see below).

Via apoptosis, or programmed cell death, myoFbs (or a subpopulation of myoFbs) are generally reduced in number at sites of repair involving the heart^33,93; with skin injury, they completely disappear.^108,109 Apoptosis does not elicit an inflammatory cell response and subsequent fibrosis.¹¹⁰ In the infarcted heart, myoFbs persist at the MI site long after infarct healing has been completed.⁸⁵ In the kidney injured by experimental glomerulonephritis, persistence of myoFbs is associated with a progressive interstitial fibrosis.¹⁰³ Irrespective of the location or nature of the inciting stimulus to connective tissue formation in the heart, myoFbs are the dominant cell involved in matrix formation.⁸⁶

	Angiotensin II and Tissue Repair in the Heart and Other Organs

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
The heart's healing paradigm, while still under investigation, probably does not differ from that of other organs. Regulatory peptides, or cytokines such as TGF-ß₁, contribute to fibrogenesis. TGF-ß₁ has numerous actions on the extracellular matrix.¹¹¹ It also contributes to chemotaxis, phenotype transformation, and proliferation of fibroblasts and scar tissue remodeling.^99,112 TGF-ß₁ mRNA is expressed in infarcted myocardium soon after coronary artery ligation^100,101 or catecholamine-induced necrosis.¹¹³ In cultured human cardiac fibroblasts, TGF-ß₁ increases transcription of both type I collagen and TIMP.¹¹⁴ Factors governing expression of TGF-ß₁ and its receptors in injured heart require investigation. Ang II augments TGF-ß₁ gene expression via AT₁ receptor binding in cultured neonatal or adult rat cardiac fibroblasts and myoFbs,^115,116 whereas endogenous elevations in circulating Ang II are associated with upregulation of the TGF-ß₁ gene in the adult rat heart.¹¹⁷ Macrophages, clustered at sites of tissue injury,¹¹⁸ are a likely source of TGF-ß₁¹⁰² that may be important to the appearance of the myoFb phenotype⁹⁹ and suppression of further inflammatory cell responses.¹¹⁹ A subsequent elaboration of TGF-ß₁ by myoFbs is integral to fibrogenesis, whereas persistence of myoFbs elaborating TGF-ß₁ leads to progressive fibrosis.¹⁰³ What induces the expression of TGF-ß₁ by macrophages and myoFbs? Ang II appears to play a central role in the expression of TGF-ß₁ by activated macrophages and myoFbs in that an AT₁Ra, given at the time of tissue injury, prevents these responses.¹²⁰

Localization of ACE and Ang II Receptors and ACE Activity
The role of Ang II in the fibrogenic phase of tissue repair has recently come under investigation. Requisite factors for the involvement of this peptide in tissue repair include its local production at functionally relevant concentrations and the presence of stereospecific Ang II receptors on cells that regulate collagen turnover.

The localization and density of ACE binding in the normal and injured heart have been examined with quantitative in vitro autoradiography and an iodinated derivative of lisinopril (¹²⁵I-351A).^{33,86,121–125} In the normal heart, low-density ACE binding is found throughout ventricular myocardium and atria, whereas high-density binding is present at sites of high collagen turnover, including heart valve leaflets and the adventitia of intramyocardial coronary arteries.^125–128 High-density ACE binding is likewise found in subcutaneous skin, with its metabolically active fibroblasts, but not skeletal muscle tendon, in which fibrocytes are quiescent.¹²⁵ Immunolabeling with a monoclonal ACE antibody¹²⁹ identified cells expressing this ectoenzyme. They include endothelial cells on the surface of each valve leaflet; myoFb-like cells, also called valvular interstitial cells, residing within leaflet matrix, where they are responsible for collagen turnover; and pericytes in the adventitia of intramural vessels. Autoradiography and immunolabeling have further demonstrated ACE binding in cultured intact myoFb-like cells and in their cell membranes.¹³⁰ RT-PCR with amplification of total RNA has demonstrated the presence of ACE mRNA in these cells. Substrate utilization of membrane-bound ACE in these cells includes Ang I and, in its dual capacity as a kininase II, other chemical mediators of inflammation, such as BK and substance P. Thus, myoFb-like cells of valve leaflets have the potential to regulate local concentrations of Ang II and other mediators of tissue repair, such as TGF-ß₁, in valve leaflets. The importance of the TGF-ß family of peptides in fetal heart development, including endocardial cushion formation and heart valve induction, has recently been reported.^131,132 A role for Ang II generated by these cells in contributing to this process should be considered.

High-affinity receptors are integral to the biological activity of such ACE-related peptides. The presence of Ang II receptors in heart valves was demonstrated by autoradiography using ¹²⁵I[Sar,¹ Ile⁸]-Ang II binding.¹²⁵ Competitive binding using either an AT₁ or AT₂ receptor antagonist, losartan or PD123177, respectively, provided identification of receptor subtype. Low-density AT₁ receptor binding is present throughout the myocardium, whereas high-density binding is present in heart valve leaflets.¹²⁵ Western immunoblot, as well as binding assay, confirmed these findings in membranes.¹³⁰ Heart valves and myoFbs membranes likewise contain BK receptors, as seen by ¹²⁵I[Tyr⁸]-BK autoradiographic binding¹²⁵ and binding assay.¹³⁰

Cellular responses to Ang II receptor–ligand binding has been examined in serum-deprived, cultured myoFb-like cells obtained from adult rat heart valve leaflets. By in situ hybridization, these cells express the transcript for type I collagen, and incubation of cultured cells with Ang II in pathophysiological concentrations enhances type I collagen synthesis via AT₁ receptor binding.^130,133,134 Immunohistochemistry^130,135 and electron microscopy^136,137 have shown that these cells and pericytes each contain -SMA microfilaments. These microfilaments confer contractile behavior to these cells, and various substances, including Ang II, promote their contraction.^136,137

Collectively, these findings implicate a biological role for ACE in the local regulation of Ang II and BK at normal tissue sites where collagen turnover is high. These findings led to additional autoradiographic and morphological studies in the rat in several different models of experimental tissue injury involving the heart, related structures, or systemic organs.

High-density autoradiographic ACE binding was found at the site of MI at week 1 and increased progressively over the course of 8 weeks (see Fig 2C) in parallel with morphological evidence of fibrillar collagen accumulation found in serial heart sections.³³ ACE activity, as measured by substrate conversion, is increased in aneurysmal tissue of the infarcted LV compared with atrial tissue.²⁹ In addition, a significant correlation was found between ACE activity and the extent of infarction,²⁹ as is also the case for ACE mRNA expression and activity at sites remote from the MI.³⁰ In the rat model of MI, the circulating RAAS is not activated.^30,138–141

By use of either monoclonal (see Fig 3B) or polyclonal ACE antibodies, ACE-labeled cells at sites of healing were identified.^33,84,142 After cardiac myocyte necrosis, they include macrophages, -SMA–positive myoFbs, and endothelial cells of the neovasculature. High-density ACE binding is also found at sites of fibrosis remote from the MI (see Fig 2C). This includes endocardial fibrosis of the interventricular septum, interstitial fibrosis of the right ventricle, the fibrosed pericardium that follows pericardiotomy (with or without infarction), and the foreign-body fibrosis that surrounds the silk ligature placed around the left coronary artery as part of a sham operation. The anatomic coincidence between high-density ACE binding and fibrosis has been observed in other injured organs of the rat, including the infarcted kidney and incised skin sutured with silk ligature.¹²³ Immunolabeling demonstrated myoFbs containing -SMA as cells expressing ACE at each of these noninfarcted related sites (see Fig 3C and 3D). High-density ACE binding is also observed at sites of isoproterenol-induced myocyte necrosis.^143,144 At all of these sites of repair, in situ hybridization and immunolabeling demonstrated myoFbs as expressing genes encoding for type I and III collagens.^33,84

In vitro quantitative autoradiography was likewise used to address Ang II receptor binding in the infarcted rat heart, with receptor subtype determined by displacement with an AT₁ (losartan) or AT₂ (PD 123177) receptor antagonist.^{135,145–147} Marked AT₁ receptor binding density is present at the site of MI and endocardial and pericardial fibrosis (see Fig 2D), whereas AT₂ receptor binding is low at these sites. Cells expressing AT₁ receptors at sites of injury are myoFbs (see Fig 3E and 3F).¹⁴⁸ These autoradiographic findings are consistent with the increase in gene transcription and protein expression of the AT₁ receptor found in homogenized tissue taken from the site of MI and remote sites by RT-PCR and binding assays.^149,150 AT₁Ra abrogates this response, which is not the case for an AT₂Ra. Increased expression of Ang II receptors likewise appears in other organs at sites of injury, such as skin.^151–153

In an isolated, crystalloid-perfused organ preparation, the conversion of Ang I to Ang II by epicardium of normal rat hearts was contrasted to hearts with fibrosis of the visceral pericardium 4 weeks after pericardiotomy (without MI).³⁴ ACE activity of the fibrosed pericardium was severalfold higher than in the normal heart, and Ang II generation was completely abrogated by ACEI. This finding also suggests that in rats, an alternative Ang II–generating pathway (eg, a chymase) is not operative in fibrous tissue. High-density ACE binding is likewise present in the perivascular fibrosis and microscopic scars that appear in the right and left atria and ventricles with the chronic administration of Ang II or aldosterone (in uninephrectomized rats on a high-sodium diet).^19,121 These latter models demonstrate that ACE binding density within fibrous tissue is independent of circulating Ang II or aldosterone, in contrast to endothelial ACE of the pulmonary artery, which is subject to negative feedback regulation by circulating Ang II.¹⁵⁴

The anatomic coincidence between the expression of ACE and AT₁ receptors with normal and pathological expressions of collagen formation is evident. High-density ACE and Ang II receptor binding, in fact, are markers of active collagen turnover. -SMA–containing, fibroblast-like cells, found within valve leaflets, adventitia, and various sites of fibrous tissue formation, express genes encoding for ACE, AT₁ receptors, and fibrillar collagens. MyoFbs could therefore be considered a "metabolic entity" regulating their own collagen turnover.⁴¹

ACE binding density is related primarily to the presence of myoFbs. The disappearance of ACE-positive cells or a reduction in their absolute number would reduce ACE binding density at sites of fibrosis. Such is the case with old sarcoid granulomas.¹⁵⁵ Both ACE and Ang II receptor binding densities in the infarcted rat heart remain high for many months after MI,^33,145 as does ACE activity.³⁰ Each is in keeping with the persistence of myoFbs at the infarct site.⁸⁵ These findings could contribute to the identification and localization of active (cellular) fibrogenesis in an organ by noninvasive technologies similar to autoradiography. Other techniques that characterize the composition of tissue, such as high-frequency ultrasound¹⁵⁶ that detects fibrillar collagen, are not dependent on the presence of ACE and myoFbs. Together, such techniques could identify the relative age of fibrosis and its cellularity, which could guide interventional strategies.

De Novo Angiotensin II Generation
Granulation tissue and its diverse cell populations in particular generate peptides integral to tissue repair via receptor-ligand binding. ACE, for example, regulates local concentrations of Ang II and BK. At the infarct site, the concentration of Ang II is increased severalfold above that found in viable myocardium.¹³⁹ De novo Ang peptide generation requires expression of several requisite components: angiotensinogen, the precursor to all Ang peptides; a protease that cleaves away amino acids from angiotensinogen to form Ang I; and ACE, which hydrolyzes the decapeptide Ang I to Ang II, an octapeptide. An independent pathway of Ang II generation involving a chymase has been suggested; however, increased expression of its transcript is infrequently found in the failing human heart.²⁸

In situ hybridization localized angiotensinogen mRNA expression in the adult rat heart and aorta to fibroblasts and brown adipocytes.^157,158 RT-PCR amplification identified angiotensinogen mRNA expression in the adult human heart.¹⁵⁹ This transcript and that of renin are localized within both neonatal fibroblasts and cardiac myocytes,¹⁶⁰ with Ang I and Ang II peptides detected in culture media.¹⁶¹ The presence of renin mRNA in normal adult heart tissue is controversial, however, and therefore, the source of cardiac renin has come into question.¹⁶² Danser et al^163–165 showed that this protease is taken up from the circulation and is of renal origin. Renin rapidly disappears from the heart after nephrectomy.¹⁶⁶ The presence of other aspartyl (eg, cathepsin D) or serine (eg, cathepsin G) proteases eliminates any absolute dependence on renin as a rate-dependent protease.^40,167 This is the case for cultured myoFbs that express cathepsin D and elaborate Ang I^133,168; renin mRNA and renin activity have not been detected in either cell population. Several recent studies, however, have reported renin mRNA expression in the adult rat heart.^169–171 The validity of a renin-angiotensin system in local Ang II generation awaits further investigation.

Pharmacological Modulation of Repair
Evidence supporting a contribution of locally produced Ang II in regulating myoFb collagen synthesis is obtained with pharmacological probes that interfere with local Ang II generation (ie, ACEI) or occupancy of its AT₁ receptor. Collagen formation in the heart and vasculature is rapid soon after birth. In 4-week-old rats treated with enalapril for 6 weeks, collagen formation in both the right and left ventricles, aorta, and superior mesenteric artery was retarded compared with untreated normal 10-week-old controls.¹⁷² In 4-week-old spontaneously hypertensive rats, a small dose of quinapril, which did not prevent the ultimate appearance of hypertension, prevented the expected rise in aortic collagen volume fraction compared with untreated 30-week-old spontaneously hypertensive rats.¹⁷³ Each of these studies implicates local Ang II in regulating normal collagen formation in the heart and vasculature.

Captopril and enalapril begun at or close to the onset of MI have each reduced infarct size, infarct expansion and thinning, and hydroxyproline concentration at the infarct site in dogs with coronary artery occlusion.^174–176 The potential contribution of reduced bradykinin degradation to tissue repair that would accompany ACEI is uncertain at present. Several studies suggest that BK is released after MI^76,77,177 and that a BK₂ receptor antagonist (Hoe140) attenuates collagen accumulation at the MI site.¹⁷⁸

Losartan begun on day 1 after coronary artery ligation in a dose that reduced AT₁ receptor binding by 50% reduces infarct scar area.¹⁷⁹ Moreover, the expected rise in tissue Ang II concentration found at the infarct site 3 weeks after coronary artery ligation is markedly attenuated by either delapril or TCV-116, an AT₁Ra, introduced on postoperative day 1.¹³⁹ These findings raise the prospect that the number of myoFbs or their Ang II–generating activity per cell at sites of repair may be influenced by Ang II. Other studies^149,180 have not found an AT₁Ra introduced at or soon after coronary artery ligation to influence fibrosis after MI. An explanation for these divergent findings is currently unclear. Each AT₁Ra reduced AT₁ receptor mRNA expression by 30%; therefore, drug delivery to the site of MI does not seem to be in question. The importance of drug dosage needs to be addressed.

Fibrous tissue formation at sites remote from MI have also been examined in response to these pharmacological interventions. Perindopril given 1 week after MI attenuates the endomyocardial fibrosis that appears in the nonnecrotic segment of the rat left ventricle.¹³⁸ Captopril commenced at the time of coronary artery ligation prevents the expected fibrosis of noninfarcted left and right ventricle^80,181 and the proliferation of fibroblasts and endothelial cells that appears at remote sites 1 and 2 weeks after MI.⁸⁰ Under these circumstances, captopril prevents the rise in LV end-diastolic pressure that appears in untreated or propranolol-treated rats; captopril also reduces inducibility of ventricular arrhythmias in this model.¹⁸¹ When initiated 3 weeks after MI, well after the tissue repair process has developed, captopril does not prevent fibrosis remote from the infarct site or the rise in ventricular stiffness.⁶² Losartan prevents fibrosis at remote sites,^32,64,179 but not the cellular proliferation that appears.⁶⁴ Others did not find an inhibition of types I and III collagen mRNA expression at remote sites^7,87 and have suggested posttranslational modification in collagen turnover to explain why fibrosis fails to appear at remote sites.⁷ In the model of cardiac myocyte necrosis associated with chronic Ang II administration, lisinopril attenuates subsequent scarring despite microscopic evidence of myocyte injury.¹²³ Other studies report conflicting results for an AT₁Ra with respect to the fibrosis that follows catecholamine-induced myocyte necrosis.^113,182

ACEI and AT₁Ra prevent the appearance of fibrosis in diverse organs with experimentally induced or naturally occurring tissue injury. These include pericardial fibrosis after pericardiotomy¹³⁵; tubulointerstitial fibrosis associated with unilateral ureteral obstruction,^{120,183–188} toxic nephropathy,^189–191 remnant kidney,^192–195 or renal injury after irradiation¹⁹⁶; the cardiovascular sclerosis and glomerulosclerosis that appear in stroke-prone spontaneously hypertensive rats^197–200; the interstitial pulmonary fibrosis that follows irradiation^201–203 or monocrotaline administration²⁰⁴; and the subcutaneous fibrous tissue pouch model.²⁰⁵ A more detailed review of Ang II and tissue repair involving systemic organs can be found elsewhere.²⁰⁶

Attenuation of fibrous tissue formation by ACEI and by AT₁Ra in particular in diverse organs with various forms of injury supports the importance of local Ang II in promoting fibrosis. Further evidence that this peptide influences collagen turnover has been obtained in cultured adult rat cardiac fibroblasts and myoFbs. In serum-deprived cells, incubation with Ang II in pathophysiological concentrations increases type I collagen mRNA expression and synthesis and reduces the collagenolytic activity of culture medium.^{168,207–209} The importance of Ang II–induced expression of TGF-ß₁ in contributing to this fibrogenic response has been suggested.^{70,116,206,210}

Elevated Circulating Ang II
A role for Ang II, as a local mediator of fibrosis, is suggested by studies in which circulating Ang II is chronically increased from either endogenous or exogenous sources. In experimental models associated with renal ischemia (unilateral in the case of isolated renal artery stenosis, bilateral in the case of suprarenal aortic banding), circulating Ang II is increased. Such models are associated with increased mRNA expression of renal renin, increased plasma renin activity, and circulating Ang II and downregulation of Ang II receptors.^211–213 In keeping with a role for circulating Ang II in promoting fibrogenesis, such adverse remodeling is observed in tricuspid and mitral valve leaflets, the normotensive, nonhypertrophied right and left atria and right ventricle, and the hypertensive, hypertrophied left ventricle and is preceded by increased mRNA expression for types I and III collagens in these models of renovascular hypertension.^{5,6,8,213–215} Arterioles of systemic organs likewise undergo a structural remodeling that includes medial thickening and perivascular fibrosis.^216–218

Macrophages, neutrophils, and myoFbs represent the cellular response that precedes the appearance of cardiac fibrosis in these models.^94,219 Infrarenal aortic banding, on the other hand, leads to hypertension and left ventricular hypertrophy but not fibrosis of either ventricle,²¹³ further demonstrating that regulation of cardiac myocyte growth is based on hemodynamic factors and not circulating Ang II, whereas fibrous tissue formation is dissociated from hypertrophy and related to this circulating hormone. Myocardial fibrosis in rats with unilateral^219–221 or bilateral renal ischemia^222,223 is prevented by ACEI or AT₁Ra.

Chronic infusion of Ang II by osmotic minipump leads to fibrosis of atria and ventricles, increased adventitial collagen of the normotensive pulmonary artery and hypertensive aorta, and systemic organ fibrosis.^19,121,224 Fibrosis is initially preceded by increased mRNA expression of fibronectin on day 3 and subsequently types I and III collagens and TGF-ß₁, each of which is related to proliferating fibroblast-like cells (not myocytes) located at sites of subsequent fibrosis in each ventricle.^225,226 Losartan, given in doses that either did or did not prevent an increase in arterial pressure, abrogated these responses. This was not the case for prazosin or hydralazine, which prevented hypertension, again confirming that hemodynamic factors are not involved in promoting fibrosis.^225,226 Potential mechanisms involved in the fibrogenic response associated with chronic elevations in Ang II have been reviewed elsewhere.²²⁷

Ang II and Other Modulators of Repair
Although Ang II is intimately involved in promoting tissue repair, a broader view of its relationship to other regulatory signals evoked at sites of injury is in order (see Fig 4). Ang II invokes the elaboration of stimulators and inhibitors of fibrogenesis in what constitutes a reciprocal regulation of repair.²²⁸ The relative preponderance of inhibitors versus stimulators determines healing. In a biological economy of action, these signals likewise regulate immediate homeostatic responses after injury. Stimulators of repair, such as Ang II, aldosterone, catecholamines, and ETs, promote coagulation and platelet aggregation, vasoconstriction, tachycardia and increased contractility, and renal sodium retention. Inhibitors, such as NO, BK, PGs, natriuretic peptides, dopamine, and glucocorticoids, have opposing effects on homeostasis and repair. The relative preponderance and potency of stimulators versus inhibitors determine overall responses. In advanced heart failure, for example, circulating levels of natriuretic peptides, Ang II, aldosterone, and ETs are each increased. The potency of RAAS effector hormones supersedes natriuretic peptides, with sodium retention and cardiac remodeling the final result. A discussion of the interplay that exists between Ang II and several of these stimulators and inhibitors is provided, focusing on the fibrogenic component of repair.

View larger version (11K): [in this window] [in a new window]   Figure 4. Model of reciprocal regulation that involves various stimulators and inhibitors of tissue repair induced by Ang II. Stimulators include Ang II, TGF-ß1, and ET1 and ET3. Inhibitors of repair include BK, PGE2, and NO.

A close relationship between Ang II generated at sites of injury and expression of the profibrotic cytokine represented by the TGF-ß family of peptides was suggested earlier. Binding of TGF-ß₁ with its receptors on fibroblasts, for example, regulates their expression of type I collagen and TIMP and favors fibrous tissue formation,^85,229 a response abrogated in injured tissue by ACEI or AT₁Ra. Ang II and TGF-ß₁ each regulate expression of ET by fibroblast-like cells.^230–234 ET₁ and ET₃ both regulate fibroblast collagen turnover via ET_A and ET_B receptor binding.^235–237 Antagonists of either the ET_A or ET_A and ET_B receptors prevent organ fibrosis.^238,239

Inhibitors of fibrous tissue formation express their influence on collagen turnover by reducing collagen synthesis and/or enhancing its degradation. iNOS is expressed by macrophages activated by cytokines (eg, -interferon) through transcription of genes encoding for iNOS; large amounts of NO are generated for hours at sites of injury.^240–242 NO and other nitrogen oxides produced by activated macrophages are cytostatic and cytotoxic.²⁴³ A short-term (hours) infusion of Ang II is associated with a rise in cardiac lymph cGMP, representing a release of NO from its constitutive form found in coronary vascular endothelium; an associated escape of macromolecules follows.⁷⁴ This increase in vascular permeability and appearance of proteins in the cardiac interstitial space leads to subsequent vascular and interstitial fibrosis. However, when L-NAME, a specific inhibitor of the oxidative L-arginine deiminase pathway and NOS activity, is administered together with Ang II to prevent macromolecular escape, myocardial fibrosis still appears.²⁴⁴ Such a regimen augments and accelerates the appearance of cardiac fibrosis, in keeping with the removal of NO as an inhibitor of fibroblast collagen turnover and fibrosis.²⁴⁵ Removal of NO favoring fibrous tissue formation occurs naturally at sites of repair through expression of TGF-ß₁, which inhibits iNOS mRNA translation while increasing iNOS protein degradation.²⁴⁰

Chronic administration of L-NAME alone leads to coronary vascular remodeling, including an increased wall thickness–to-lumen ratio and perivascular fibrosis, and the gradual appearance of arterial hypertension over the course of several weeks.²⁴⁶ These iterations in coronary vascular structure are not related to this rise in arterial pressure, as evidenced by rats treated with L-NAME and hydralazine in combination, who remained normotensive, or rats receiving a small dose of L-NAME that did not lead to hypertension. In each case, coronary remodeling still occurred. The importance of unopposed, local Ang II generation in promoting this remodeling is therefore suggested, and increased ACE activity is present in remodeled intramyocardial coronary arteries seen with long-term blockade of NO synthesis.²⁴⁷ ACEI prevents such L-NAME–associated remodeling by reducing local concentrations of Ang II at sites of fibrosis.

BK, like NO, is linked to inflammatory responses. BK is rapidly degraded; however, its effect is expressed via the release of other substances, such as prostaglandins.²⁴⁸ During the acute inflammatory phase that follows MI on days 1 and 4, the release of PGE₂ is markedly increased by administration of BK.²⁴⁹ Prostaglandin synthesis has been demonstrated in various mesenchymal cells, including endothelial cells, squamous epithelium of visceral and parietal pericardium, pleura, and peritoneum,^250,251 and fibroblasts of various organs.^252,253 Fibroblast-like cells isolated from infarcted tissue 7 days after coronary ligation demonstrated increased cyclooxygenase activity and PGE₂ production compared with fibroblasts of noninfarcted tissue.²⁵⁴

Ang II, BK, and PGE₂ are released by cells involved in tissue repair. The expression of angiotensinogen mRNA, measured on day 5 after MI, is increased in the left ventricle.²⁵⁵ This precedes the early morphological evidence of fibrillar collagen accumulation that appears on day 7.³³ Ang II content of infarcted tissue is increased compared with remote sites; this response is prevented by delapril.¹³⁹ At week 4 after MI, and long after the inflammatory phase has resolved, BK-induced release of PGE₂ from the heart remains increased.²⁴⁹ Even as late as 12 weeks after MI, microsomes prepared from infarcted tissue demonstrate enhanced arachidonic acid metabolism.²⁵⁶

	A Paradigm of Tissue Repair

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
Fig 5 depicts a theoretical model of tissue repair involving a two-part generation of Ang II and coordinate activation of several genes through a complex series of multicellular events. Repair begins with an early invasion of injured tissue by inflammatory cells, such as neutrophils and CD4⁺ lymphocytes that secrete -interferon, which serves to activate macrophages that have invaded the fibrin-fibronectin meshwork from the circulation and local sites. Once activated, macrophages express the gene encoding for iNOS and produce NO, which is related to their programmed cell death (apoptosis), including the macrophages that produce it.^257–259 Activated macrophages likewise express inducible cyclooxygenase that leads to their production of PGs. A phenotype conversion of macrophages is involved, given that inactive macrophages do not express ACE. This adaptation of macrophages results in their acquiring functional activity that includes expression of angiotensinogen, ACE, and cathepsin G and their ability to generate Ang II de novo.^40,260 In an autocrine manner, macrophage-derived Ang II stimulates expression of TGF-ß₁, which favors the recruitment of pluripotent interstitial fibroblasts and their conversion to the myoFb phenotype on day 4 after injury; myoFb proliferation follows. TGF-ß₁ also serves to suppress the inflammatory cell response favoring collagen formation. ACEI or AT₁Ra introduced at the time of repair or within the first 48 hours could interfere with the ultimate appearance of fibrous tissue by abrogating this first phase of Ang II generation and its important functions in cell-cell signaling and TGF-ß₁ formation.

View larger version (61K): [in this window] [in a new window]   Figure 5. After tissue repair, a complex set of cellular and molecular responses occur to eventuate in fibrous tissue formation. This includes monocytes and macrophages, which express inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (iCOX2) and whose phenotypic transformation and activation lead to cells that express ACE, angiotensinogen, and cathepsin G (catG), allowing for de novo generation of Ang II. In an autocrine manner, Ang II causes expression and release of TGF-ß1, which is integral to phenotypic transformation of recruited interstitial fibroblasts into myofibroblasts. MyoFbs are likewise able to express Ang II de novo with their expression of angiotensinogen, cathepsin D (CatD), and ACE, whose autocrine properties include expression of TGF-ß1 that is responsible for fibrogenesis, including expression (mRNA and protein levels) for types I and III collagens and TIMPs. MyoFb-generated Ang II also has paracrine functions at and remote from site of injury. It serves to promote expression of inhibitors of repair from endothelial cells of neovasculature (NO, BK, PGE2) and various steroids. Fate of fibrosis can include regression, associated with programmed cell death (apoptosis) of myoFbs, and loss of their stimulatory signals that leaves unbridled MMP activation; a persistence or progression of fibrosis is associated with persistence of myoFbs and continued elaboration of stimulatory signals and collagen turnover.

Like transformed macrophages, myoFbs express components requisite to de novo Ang II generation. This subsequent source of Ang II has an autocrine function that stimulates expression of TGF-ß₁, and it is this cytokine that determines collagen turnover at sites of repair and remote sites (Fig 5) through transcriptional regulation of fibrillar collagens and TIMPs. Fibrous tissue accumulation at both sites now commences. MyoFb-generated Ang II has several paracrine functions that serve to stimulate endothelial cells of the neovasculature to elaborate NO, BK, PGs, ETs, steroids, and TIMP-1,²⁶¹ each of which likewise contributes to inflammatory and fibrogenic events. The nature of these steroids is not fully understood. It has been suggested that endothelial cells elaborate aldosterone,^262,263 whereas spironolactone, an aldosterone receptor antagonist, inhibits angiogenesis.²⁶⁴ The potential for local steroidogenesis at sites of repair and the influence of such steroids on healing remains to be examined.

Once fibrous tissue has been deposited and the extracellular matrix remodeled (eg, wound closure of skin), myoFbs are reduced in number and eventually disappear through apoptosis, or programmed cell death.¹⁰⁹ An activation of MMPs and absence of Ang II and TGF-ß₁ may actually lead to a regression of fibrosis, as is the case in skin. Persistence of myoFbs or a particular subpopulation of myoFbs, with continued expression of Ang II and TGF-ß₁, is accompanied by low-grade collagen turnover, as is the case for the permanent scar that appears at the site of MI.^85,86 Under circumstances in which myoFbs persist or a subpopulation increases in number, a progressive fibrosis will result.¹⁰³ The pathophysiology accounting for regressive, persistent, and progressive fates of fibrosis remains to be elucidated. Insights into these various events should shed light on the development of cardioprotective and reparative strategies. In addition, a broader understanding of fibrillar collagen expression²⁶⁵ and the tissue repair paradigm¹¹⁹ may provide other means by which to interfere with unwanted fibrosis—a final pathway to cardiac failure.

	Ang II, DD, and the Clinical Vignette Revisited

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
Mindy Carson was correct. The cellular composition of fibrous tissue, ie, its myoFbs and their cell-cell and cell-matrix connections, lends it its contractile behavior. Contraction of this cellular–fibrous tissue assembly accounts for matrix remodeling at the site of repair, such as closure of an open skin wound and scar thinning in the case of the infarcted heart. The contractile behavior of fibrosed palmar fascia accounts for retraction of involved fingers, such as Dupuytren's contracture in Joseph McKenzie's hand. Fibrosed organs and rings of fibrous tissue demonstrate contractile behavior (see Fig 6). Contraction occurs within minutes on exposure to such substances as Ang II, catecholamines, ET₁, PGE₂, or 5-hydroxytryptamine, whereas relaxation is produced by papaverine.^{98,230,266,267} Similar contractile behavior has been observed in transverse strips of scar tissue obtained from the rat heart 5 weeks after MI.²⁶⁸

View larger version (22K): [in this window] [in a new window]   Figure 6. Fibrous tissue is a contractile assembly based on myoFbs having -SMA and cell-cell connections via gap junctions and cell-matrix connections via a fibronexus. Contraction of assembly, which accounts for scar contraction and thinning, is promoted by Ang II, ET1, PGE2, 5 hydroxytryptamine (5HT), or norepinephrine (NE). Relaxation is promoted by papaverine. Adapted from Weber KT. Cardiac interstitium. In: Poole-Wilson PA, Colucci WS, Massie BM, Chatterjee K, Coats AJS, eds. Heart Failure: Scientific Principles and Clinical Practice. New York, NY: Churchill Livingstone; 1997:13–31.

DD of either the right or left ventricle, either form of which has been demonstrated to be of importance in patients with heart failure,^50,269 is related to factors extrinsic to the ventricular chamber (eg, right and left heart interaction, fibrosed pericardium) and to those intrinsic to its myocardium (eg, fibrous tissue, abnormalities in sarcoplasmic calcium uptake), which can influence relaxation and passive stiffness. The multiple lines of evidence reviewed in this report would suggest that a broader perspective of DD is warranted. Whether expressed in the form of a macroscopic scar after MI or as microscopic fibrosis, such as appears remote from an MI or with chronic RAAS activation, fibrous tissue has the potential for contractile behavior, based on the presence of myoFbs.

In hopes of shedding more light on this subject, earlier observations pertaining to administration of Ang II or ACEI on DD in experimental animals and diseased human myocardium are briefly reviewed. These informative studies were undertaken in view of the early recognition of a relationship between increased ACE activity and hypertrophy found in a rat model of suprarenal aortic banding. It is now appreciated that the localization of high-density ACE binding (and activity) is confined to sites of fibrosis that appear in both the hypertrophied ventricle and nonhypertrophied ventricle and atria, pericardium, and systemic organs. ACE binding is independent of the pattern of hypertrophy (concentric versus eccentric), hemodynamic factors, and circulating Ang II.

In isolated normal rat hearts, in which left ventricular diastolic volume was experimentally fixed (an isovolumic preparation), intracoronary infusion of Ang II did not influence end-diastolic pressure.²¹² This same preparation was used to study the hypertrophied left ventricle observed in rats 8 weeks after suprarenal aortic banding. A reactive and reparative fibrosis coincident with high-density ACE binding and myoFbs at these sites (see above) is likewise expected. Administration of Ang II led to a 50% increase in filling pressure of the isovolumic ventricle, which could be prevented by losartan but not an AT₂ receptor antagonist.²¹² This finding supports my contention that fibrous tissue contraction, as well as proposed alterations in cardiac myocyte calcium homeostasis, can contribute to DD.

In patients with severe LVH, hypertension, and elevated end-diastolic pressure, in whom myocardial fibrosis is expected,^270,271 a 30-minute left coronary artery infusion of enalaprilat at a dose that did not affect heart rate or systemic vascular resistance led to an acute fall in filling pressure.²⁷² A similar intracoronary infusion of enalaprilat for 15 minutes led to an acute reduction in left ventricular end-diastolic pressure and improvement in diastolic distensibility in patients with LVH and significant aortic valvular stenosis.²⁷³ Fibrosis is a well-recognized accompaniment of the structural remodeling found in aortic stenosis.^274–276 Benazeprilat given intravenously led to an acute reduction in end-diastolic pressure and diastolic wall stress in patients with coronary artery disease and previous transmural MI, and this response was noted in asymptomatic and symptomatic patients with cardiac failure.²⁷⁷

Collectively, these findings serve to suggest that the salutary response to ACEI in cardiac failure may include an improvement in DD and may be related to relaxation of fibrous tissue and the tension it exerts within the fibrosed and hypertrophied myocardium.

	Summary and Future Directions

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
A structural remodeling of the extracellular matrix is an important determinant of abnormal ventricular function and reduced threshold for arrhythmia(s) in chronic cardiac failure. Phenotypically transformed fibroblast-like cells, or myoFbs, appear at sites of repair and are responsible for fibrogenesis. The contribution of myoFbs to repair in the heart is independent of the etiologic basis of injury, the location of repair, hemodynamic factors, hypertrophy, or circulating RAAS activation. At sites of repair, myoFbs express components requisite to de novo generation of Ang II, which has important autocrine and paracrine properties that regulate various molecular and cellular components of repair, including expression of the fibrogenic peptide TGF-ß₁.

	Selected Abbreviations and Acronyms

 

ACEI = ACE inhibitor Ang II = angiotensin II AT1, AT2 = angiotensin II subtype I and II receptors AT1Ra = angiotensin II subtype I receptor antagonist BK = bradykinin DD = diastolic dysfunction ET = endothelin iNOS = inducible nitric oxide synthase L-NAME = nitro-L-arginine methyl ester LVD = left ventricular dysfunction MI = myocardial infarction MMP = matrix metalloproteinase myoFb = myofibroblast NO = nitric oxide PGE2 = prostaglandin E2 RAAS = renin-angiotensin-aldosterone system RT-PCR = reverse transcriptase–polymerase chain reaction TGF-ß1 = transforming growth factor-ß1 TIMP = tissue inhibitor of MMP -SMA = -smooth muscle actin

	References

Top Introduction Clinical Vignette: Bee Stings... Ventricular Dysfunction and the... Cardiac Remodeling and the... Angiotensin II and Tissue... A Paradigm of Tissue... Ang II, DD, and... Summary and Future Directions References

 
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