Published online before print April 6, 2009, doi: 10.1161/CIRCULATIONAHA.108.826230
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(Circulation. 2009;119:2086-2095.)
© 2009 American Heart Association, Inc.
Molecular Cardiology |
Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog
From the Center for Heart Failure Research, Departments of Medicine (J.Z., Y.C., B.P., L.A.D., P.C.P., K.S., N.S., A.H., L.J.D.) and Physiology and Biophysics (A.H.), University of Alabama at Birmingham; Birmingham Department of Veteran Affairs, Birmingham, Ala (L.J.D.); and Auburn University College of Veterinary Medicine (M.T., A.R.D.) and School of Engineering (T.D.), Auburn, Ala.
Reprint requests to Louis J. Dell'Italia, MD, University of Alabama at Birmingham Center for Heart Failure Research, Division of Cardiology, 434 BMR2, 1530 3rd Ave S, Birmingham, AL 35294-2180. E-mail loudell{at}uab.edu
Received October 5, 2008; accepted January 30, 2009.
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Abstract |
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Background— The volume overload of isolated mitral regurgitation (MR) in the dog results in left ventricular (LV) dilatation and interstitial collagen loss. To better understand the mechanism of collagen loss, we performed a gene array and overlaid regulated genes into ingenuity pathway analysis.
Methods and Results— Gene arrays from LV tissue were compared in 4 dogs before and 4 months after MR. Cine-magnetic resonance–derived LV end-diastolic volume increased 2-fold (P=0.005), and LV ejection fraction increased from 41% to 53% (P<0.007). LV interstitial collagen decreased 40% (P<0.05) compared with controls, and replacement collagen was in short strands and in disarray. Ingenuity pathway analysis identified Marfan syndrome, aneurysm formation, LV dilatation, and myocardial infarction, all of which have extracellular matrix protein defects and/or degradation. Matrix metalloproteinase-1 and -9 mRNA increased 5- (P=0.01) and 10-fold (P=0.003), whereas collagen I did not change and collagen III mRNA increased 1.5-fold (P=0.02). However, noncollagen genes important in extracellular matrix structure were significantly downregulated, including decorin, fibulin 1, and fibrillin 1. In addition, connective tissue growth factor and plasminogen activator inhibitor were downregulated, along with multiple genes in the transforming growth factor-β signaling pathway, resulting in decreased LV transforming growth factor-β1 activity (P=0.03).
Conclusions— LV collagen loss in isolated, compensated MR is chiefly due to posttranslational processing and degradation. The downregulation of multiple noncollagen genes important in global extracellular matrix structure, coupled with decreased expression of multiple profibrotic factors, explains the failure to replace interstitial collagen in the MR heart.
Key Words: extracellular matrix • gene expression microarray analysis • left ventricle • mitral regurgitation • TGF-beta
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Introduction |
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The extracellular matrix (ECM) is a heterogeneous amalgam of macromolecules that are capable of self-assembly into a multimeric structure that contributes to the scaffolding of cells in the heart. In addition to collagen, the multimeric structure contains molecules that stabilize collagen and contribute to integrity of the entire ECM by connecting individual cardiomyocytes and cardiomyocyte bundles in a laminar structure. This structural organization maintains ventricular shape and provides for transmission of forces during systole across the myocardial wall.1 An intact ECM is maintained in pressure overload. However, over time, pressure overload produces concentric left ventricular (LV) and cardiomyocyte hypertrophy and LV fibrosis.2 In contrast, the volume overload of isolated mitral regurgitation (MR) in the dog produces eccentric LV remodeling, which is characterized by LV dilation and wall thinning, cardiomyocyte elongation, and a decrease in interstitial collagen.3–5 We have shown that interstitial collagen loss within 12 hours after the volume overload of aortocaval fistula in the rat causes LV dilatation. This precedes cardiomyocyte elongation, suggesting that collagen breakdown is the first step in the pathophysiology of LV dilatation in response to a pure volume overload.6
Clinical Perspective p 2095
Evidence from our dog model of isolated MR suggests that persistent loss of interstitial collagen is central to chronic eccentric LV and cardiomyocyte remodeling, but the molecular basis remains unclear. This is an important question because currently no recommended medical therapy is available to attenuate LV remodeling and thereby delay the need for valve surgery in patients with isolated MR.7 Chronic angiotensin-converting enzyme inhibition5,8 and angiotensin II receptor blockade,9 which reduce cardiomyocyte remodeling and collagen accumulation in pressure overload, do not attenuate LV dilatation, cardiomyocyte elongation, and interstitial collagen loss in the dog model of isolated MR. This illustrates that concentric remodeling in pressure overload and eccentric remodeling in isolated MR have different underlying mechanisms of ECM turnover and synthesis.
We have shown that eccentric LV remodeling in isolated, compensated MR is associated with increased matrix metalloproteinase (MMP) activity, loss of interstitial collagen, and cardiomyocyte elongation.4,5 Animal models of aortocaval fistula in the rat and pacing tachycardia in the pig have shown that MMP inhibition significantly attenuates LV dilatation by preventing interstitial collagen loss, implicating collagen degradation in the pathophysiology of LV remodeling and heart failure.10,11 Here, we report a more global defect of ECM homeostasis. Using gene array, we not only found marked increases in MMP gene expression but also significant decreases in the expression of critical noncollagen ECM scaffolding protein and glycoprotein genes, as well as a decreased expression of multiple profibrotic growth factors in the LV myocardium of dogs with chronic isolated MR.
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Methods |
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Creation of MR
Mitral valve regurgitation was induced at Auburn University College of Veterinary Medicine in conditioned mongrel dogs of either sex (weight, 19 to 26 kg) by chordal rupture as described previously in our laboratory.3–5,9 Magnetic resonance imaging (MRI) and LV hemodynamics were performed in all dogs before MR induction and after 4 months of MR under isoflurane anesthesia. Biopsies were taken from the LVs of each dog before induction of MR. Animals were transported to the University of Alabama at Birmingham for the terminal experiments. This study was approved by the Animal Resource Programs at University of Alabama at Birmingham and Auburn University College of Veterinary Medicine.
Magnetic Resonance Imaging
Dogs were anesthetized with isoflurane anesthesia, and cine-MRI was performed with a Picker Vista 1.0-T magnet. Endocardial and epicardial contours were traced manually on the LV end-diastolic (ED) and end-systolic (ES) images. The contours were traced to exclude the papillary muscles. LVED and LVES volumes were determined by summing serial short-axis slices as described previously in our laboratory.3,5
Euthanasia Study
Dogs were maintained under a deep plane of isoflurane anesthesia and were mechanically ventilated (Harvard Apparatus, Inc). The heart was arrested as described previously in our laboratory.3,5 The LV was cut into pieces that were either perfusion-fixed with 3% paraformaldehyde, snap-frozen in liquid nitrogen, or placed in an RNA stabilizing solution (RNA later, Qiagen Sciences) for subsequent analyses.
RNA Isolation
Total RNA was extracted from LV biopsies before MR induction and at 4 months of MR with the Qiagen RNeasy Fibrous Tissue Mini Kit (Qiagen Sciences). DNase I (Qiagen Sciences) was applied to remove genomic contamination. Negative reverse transcription polymerase chain reaction (RT-PCR) with the use of GAPDH primers (Table 1) ensured no genomic contamination. Integrity of the RNA was evaluated on the BioRad Experion (Bio-Rad Laboratories, Hercules, Calif). Samples with optical density ratio 260/280 >1.8, 28S/18S >1.5 were selected for microarray processing.
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Microarray Analysis
Two-color microarrays were performed on Agilent 4x44 canine array chips with 42 000+ predicted Canis familiari genes following established Agilent 2-color protocol (Agilent Technologies). Comparative analysis between expression profiles for Agilent experiments was performed with the use of Genespring GX 7.3.1 (Agilent Technologies). Gene expression data were normalized in 2 ways: per chip normalization and per gene normalization. Dye swap hybridizations were merged with their counterparts, with the average of the 2 values for a spot taken as the representative value. A gene list was generated containing a 24 196 gene sequences flagged as present. The "present" list was then filtered with the use of "filter by expression," "self confidence," and "Benjamini and Hochberg false discovery test." Significant genes were selected with a cutoff of P<0.05 and fold change >1.5.
Ingenuity Pathway Analysis
The selected genes were subsequently analyzed with the use of ingenuity pathway analysis (IPA) 5.0 (Ingenuity Systems Inc). Functions and pathways, which were predicted to be influenced by the differentially expressed genes, were ranked in order of significance and further analyzed by overlaying with cardiovascular function and disease.
Verification of Gene Expression With Real-Time RT-PCR
Quantitative real-time PCR was performed with the use of the Bio-Rad iCycler iQ system (Bio-Rad Laboratories) on 500 ng total RNA from microarray samples to verify array data. Selected genes and primer sequences (Sigma-Genosys, Woodlands, Tex) are presented in Table 1. GAPDH was chosen as an endogenous control.
Western Blot for Decorin, Integrin 
V, Transforming Growth Factor-β Receptor 2, Smad7, and Phospho-Smad2
Forty micrograms of total protein from LV endocardium of normal and 4-month MR dogs was subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by Western blot analysis. Primary antibodies used were decorin (H-80) (Santa Cruz Biotechnology, Inc, Santa Cruz, Calif), integrin V (Abcam, Cambridge, Mass), transforming growth factor (TGF)-β receptor 2 (TGF-βR2) (C-16) (Santa Cruz Biotechnology, Inc), smad7 (Santa Cruz Biotechnology), and phospho-smad2 (Ser465/467) (Upstate Cell Signaling Solutions, NY), respectively. Membranes were stripped and reblotted with anti-tubulin (Sigma-Aldrich, St Louis, Mo) as a loading control.
Immunohistochemistry for Phospho-Smad2 and Mast Cells Chymase
Immunohistochemistry was performed on formalin-fixed, paraffin-embedded LV endocardium with the use of antibodies for phospho-smad2 (Ser465/467) (Upstate Cell Signaling Solutions) and dog chymase (kindly provided by Dr George H. Caughey, University of California, San Francisco) in normal and 4-month MR dogs. Mast cells were stained with dog chymase antibody and counted for 36 fields randomly chosen at x40. Total mast cell number was divided by the tissue area to yield the number of mast cells per square millimeter.
TGF-β1 Activity
Sixty to 100 mg LV endocardium and epicardium were homogenized in PBS (pH 7.4) containing complete protease inhibitor (Roche Diagnostics, Mannheim, Germany) and centrifuged at 12 000g for 10 minutes. Total protein in the supernatant was measured with a Bradford protein assay kit (Bio-Rad Laboratories). TGF-β1 activity was determined by a commercial enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minn). TGF-β1 activity was expressed per milligram of protein in each sample.
Total Collagen Analysis
LV endocardial total collagen was determined by the hydroxyproline method according to a previously described colormetric method.12 Morphological evaluation of volume percent collagen was performed on tissues from normal dogs and 4-month MR dogs by picric acid sirius red as described previously in our laboratory.13
Statistical Analysis
Data are presented as mean±SEM. Comparison within groups (magnetic resonance LV volumes) was tested by paired t test (RT-PCR) or unpaired t test between control and MR dogs (Western blot, collagen analysis). A P value of <0.05 was considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Morphometry, MRI, and Hemodynamics
LV mass to body weight ratio increased in MR versus normal dogs (3.9±0.2 to 4.9±0.3 g/kg; P=0.04). Total LV endocardial collagen by hydroxyproline was decreased 35% (P<0.05), and interstitial collagen volume fraction decreased 40% (P<0.05) in 4-month MR dogs versus normal dogs (Figure 1). Hemodynamics and LV volumes and function were recorded before MR induction and 4 months after MR at the time of euthanasia. In MR dogs, LVED volume increased from 34±4 to 64±9 mL (P<0.005) as LVES volume increased from 20±4 to 31±8 mL (P<0.03), resulting in a 3-fold increase in stroke volume (13±1 to 33±2 mL; P<0.006). Cardiac output decreased from 4.14±0.56 to 3.14±0.44 L/min (P<0.005) as LVES pressure remained unchanged from baseline, suggesting a decrease in LV function, consistent with a decrease in SERCA2 expression (Figure 2). LVED pressure increased from 10±2 to 19±3 mm Hg (P<0.03), and LV ±dP/dtmax did not change; however, LV ejection fraction increased from 41±5% to 53±6% (P<0.007) after 4 months of MR (Tables 2 and 3
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Microarray Analysis
A total of 659 genes were differentially expressed by at least 1.5-fold in MR dogs (P<0.05), including 217 upregulated and 442 downregulated genes. The heat map in Figure 3A demonstrates a consistent pattern of change of these genes in the 4 MR dogs. Table 4 lists genes well established in the pathophysiology of cardiovascular disease that were altered >1.5-fold. Figure 3B lists noncollagen ECM genes that were downregulated >1.5-fold. These include microfibrillar genes fibrillin 1 and fibulin 1 and glycoprotein genes including multimerin 1, vitronectin, decorin, versican, and lumican. In addition, significant downregulation of integrin V occurs. Plasminogen activator inhibitor type 1 (PAI-1), thrombospondin 1, TGF-βR2, TGF-β receptor 3 (TGF-βR3), and connective tissue growth factor (CTGF) are significantly downregulated, whereas MMP-1 and MMP-9 are increased 5- and 10-fold, respectively (Figure 3B, 3C).
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Validation of Microarray With Quantitative PCR
Table 5 demonstrates the validation of the microarray results for von Willebrand factor, TGF-βR2, TGF-βR3, fibulin 1, lumican, fibrillin 1, decorin, PAI-1, KITLG, MMP-1, and MMP-9 by quantitative RT-PCR.
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Clustering Gene Expression Patterns
The 659 canine genes that changed >1.5-fold were matched to the human ID according to their sequence identity, and 322 genes were mapped in IPA, resulting in a network score of 52 for dermatological diseases (Figure 4). Genes in this network collectively define an association between ECM loss and edema in skin diseases, such as bullous pemphigoid, that are mast cell dependent. Indeed, we found an increase in mast cell numbers in these MR dogs (Figure 5), as reported previously in our laboratory.4,5 Overlaying this network with cardiovascular function and disease identified Marfan syndrome, aneurysm formation, LV dilatation, vascular injury, and myocardial infarction, all of which are characterized by ECM protein defects, degradation, or both.
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Quantification of Integrin V, Decorin Protein, and TGF-β1 Activity
Integrin V protein expression was significantly decreased in 4-month MR versus normal dogs (Figure 6A), and decorin protein demonstrated a strong trend to decrease in MR dogs (P=0.08) (Figure 6B). Phospho-smad2 was significantly decreased in the MR LV (Figure 7A through 7C) and is in a nuclear location, as demonstrated in Figure 7B. Protein expression of TGF-βR2 (Figure 7D) was significantly decreased in MR versus normal dogs. Smad7 (Figure 7E), which is a negative regulator of TGF-β1 activity, was upregulated and TGF-β1 activity (Figure 7F) was decreased in MR LV.
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Discussion |
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LV dilatation and remodeling have been associated with a breakdown of interstitial collagen and increased expression and activation of MMPs in models of heart failure10,11 and in isolated MR.3–5 Here, for the first time, we report a global decrease in the ECM with downregulation of multiple noncollagen microfibrillar and glycoprotein genes essential to collagen assembly and total ECM structure. Furthermore, in the face of increased expression of MMP genes, expression decreases of growth factor genes and the TGF-β signaling pathway that control synthesis of these ECM components. This could explain the failure of orderly replacement of interstitial collagen, resulting in cardiomyocyte and myofiber slippage and adverse eccentric LV remodeling in isolated MR.
The 4-month stage of MR has a 2-fold increase in LVED volume but an increase in LV ejection fraction, supporting a relatively compensated state rather than overt failure. IPA identified Marfan syndrome, aneurysm formation, myocardial infarction, and LV dilatation (Figure 4). All of these disorders are marked by ECM protein defects and/or ECM degradation. Indeed, MMP-1 and -9 are highly upregulated and occupy a central location in the IPA map in Figure 4; however, a striking downregulation of multiple essential noncollagen ECM genes also occurs (Figure 3B). Of these genes, decorin is the most abundant in the normal heart and is associated with all major types of collagens.14 It colocalizes with large helical collagen fibers15 and binds to specific sites on collagen molecules as they assemble, increasing the tensile strength of uncross-linked collagen fibers.16 Decorin-null mice have more severe LV dilation after experimentally induced myocardial infarction.17 In our MR dogs, collagen I mRNA was unchanged and collagen III1 mRNA was increased 1.5-fold, whereas total collagen was decreased by 35%, suggesting a posttranslational degradation. Analysis of collagen showed diffuse endomysial collagen loss with short strands randomly distributed in the LV (Figure 1). With the decrease in decorin mRNA and protein in the MR LV, it is tempting to speculate that decreased decorin resulted in less stable collagen, making it more prone to degradation, which is identified as a direct interaction of MMP-9 on decorin by IPA (Figure 4).
The ECM is made of a collection of noncollagen microfibrils and glycoproteins that serve to connect collagen to cell surfaces and promote cell-cell interactions. Fibrillin 1 is the major component of extracellular microfibrils distributed throughout perivascular and perimysial areas.18 Fibrillin-1 gene mutations are responsible for Marfan syndrome,19 whereas fibulins are implicated in elastic matrix fiber assembly, structural integrity, and function.20 Multimerin,21 versican,22 lumican,23 and vitronectin24 are important ECM glycoproteins that are also downregulated in the MR heart. These molecules link microfibrils, such as fibrillin, elastic fibers, and collagen, to cell surfaces, as indicated by adhesion of fibronectin matrix to versican defects in the IPA map.
It is of note that integrin v is also downregulated. Integrins mechanically link the cytoskeleton to the ECM in cardiomyocytes and are important in transducing mechanical signals to the cardiomyocyte. Integrins, including integrin v, as well as phosphorylation of focal adhesion kinase (FAK), have been shown to be upregulated in pressure overload.25 In 4-week MR dogs, we found a decrease in FAK tyrosine phosphorylation along with FAK interaction with adapter and cytoskeletal proteins p130Cas and paxillin.26 In contrast, FAK phosphorylation is upregulated in pressure overload, and its silencing attenuates the increase in collagen content and fibrosis in response to pressure overload.27 IPA identified downregulation of epidermal growth factor receptor in 4-month MR LVs. Epidermal growth factor receptor stimulation triggers a cascade of events that affect cell morphology, FAK phosphorylation, and phosphorylation of many cytoskeletal proteins and has been associated with growth and aggressiveness of tumors.28 A loss of ECM and its signals to the cell surface could result in decreased integrin and epidermal growth factor receptor expression in MR.
Central to the decrease in ECM component synthesis is the downregulation of the group complex of TGF-β and of CTGF, which are both increased in models of pressure overload.29 TGF-β regulates decorin, fibulin, and fibrillin production,30,31 and downregulation of the TGF-β group complex was verified by significant decreases in phosphorylated smad2 and TGF-β1 activity in the MR LVs. CTGF mediates interactions with growth factors, integrins, and ECM components and is required for ECM production. In the CTGF knockout mouse, a decrease is seen in chondrocyte proliferation, tensile strength of cartilage, and growth plate angiogenesis.32 CTGF also mediates TGF-β fibrotic responses by suppression of smad7 transcription,33 and binding of CTGF to TGF-β enhances TGF-β1 activity.34 Finally, a 3-fold decrease is seen in PAI-1 expression, a principal inhibitor of plasminogen activators that promotes fibrosis by preventing MMP activation and ECM degradation by plasminogen activators and plasmin.35 PAI-1 is upregulated markedly early in the course of pressure overload in the mouse heart.36 Thus, IPA identified downregulation of multiple growth factors that are central to ECM integrity.
IPA also identified marked upregulation of the chemokine proplatelet basic protein,37 adhesion molecules selectin L and selectin P, and stem cell factor KITLG, resulting in links to vascular injury, myocardial infarction, degranulation of granulocytes, and mast cells (Figure 5). This inflammatory feature is consistent with our finding of an early and persistent increase in mast cells and chymase activity in the MR dog.4 Mast cells contain a collection of cytokines and proteolytic enzymes, including tryptase and chymase, which activate MMPs.38 Indeed, mast cell tumors in dogs have increased MMP-2 and -9 activity that predicts tumor invasion and histological score.39 In the volume overload of aortocaval fistula in the rat, mast cell stabilization attenuates LV dilatation, presumably by inhibiting MMP activation.40 Thus, influx of mast cells and other inflammatory cells could be responsible for the increase in MMPs as well as their activation via their inflammatory cell proteases, but the increase in MMP mRNA also suggests production from resident cardiac cells such as fibroblasts.
Increased interstitial fibrosis, replacement fibrosis, and perivascular fibrosis have been identified in many forms of heart failure, especially in response to pressure overload. In contrast, here we report downregulation of profibrotic factors in MR in the face of an inflammatory gene and mast cell response. Although this may allow for a more compliant LV to accommodate the volume load, the loss of collagen and noncollagen ECM components may permit excessive LV dilatation. The loss of collagen has been a consistent finding in all of our studies of this dog model for up to 6 months after MR induction.4 Beeri and coworkers41 reported greater activation of MT-1 MMP in the remote region of a sheep model of apical infarction combined with LV to left atrial shunt of 30% compared with infarct alone, suggesting that the additional stretch of LV regurgitant shunt activated MMPs. This normalized at a later time point along with upregulation of tissue inhibitors of MMPs. Thus, our time point of 4 months may be relatively early in the time course in this model, and fibrosis may ensue at a later stage of MR, perhaps at 1 year or later.
A limitation of the this study is that a parametric test for analyzing fold gene changes with the small sample of 4 MR dogs represents a problem when it is not possible to verify that the difference data have a normal distribution. Nevertheless, protein confirmation of downregulation of the TGF-β receptor and signaling system supports the contention that this low-pressure type of volume overload induces molecular signals not only for increased MMPs but also for decreased synthesis of noncollagen ECM proteins and their growth factors. Although this may initially allow for a more compliant LV chamber, over time, persistent ECM loss leads to myocyte slippage, apoptosis,42 and cardiomyocyte dysfunction. Taken together, molecular signals that decrease synthesis in the face of increased degradation of ECM could explain why antifibrotic drugs such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers do not attenuate LV dilatation and ECM loss in the canine model of isolated MR. These findings call for a new treatment paradigm that addresses ECM loss to attenuate progressive LV dilatation in isolated MR.
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Acknowledgments |
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Sources of Funding
This study is supported by the Department of Veteran Affairs (Dr L.J. Dell'Italia) and the National Heart, Lung, and Blood Institute Specialized Center of Clinically Oriented Research in Cardiac Dysfunction (P50HL077100).
Disclosures
None.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.826230/DC1.
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