(Circulation. 1997;96:220-226.)
© 1997 American Heart Association, Inc.
Articles |
Prorenin, Renin, Angiotensinogen, and Angiotensin-Converting Enzyme in Normal and Failing Human Hearts
Evidence for Renin Binding
From the Departments of Pharmacology (A.H.J.D., C.A.M. van K., W.A.B., P.R.S.), Cardiology (M.T.), and Internal Medicine I, Cardiovasculair Onderzoeksinstituut Erasmus Universiteit Rotterdam, and Erasmus University Rotterdam (F.H.M.D., M.A.D.H.S.) (Netherlands).
Correspondence to A.H. Jan Danser, PhD, Department of Pharmacology, Room EE1418b, Erasmus University, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail danser{at}farma.fgg.eur.nl
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Abstract |
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Background A local renin-angiotensin system in the heart is often invoked to explain the beneficial effects of ACE inhibitors in heart failure. The heart, however, produces little or no renin under normal conditions.
Methods and Results We compared the cardiac tissue levels of renin-angiotensin system components in 10 potential heart donors who died of noncardiac disorders and 10 subjects with dilated cardiomyopathy (DCM) who underwent cardiac transplantation. Cardiac levels of renin and prorenin in DCM patients were higher than in the donors. The cardiac and plasma levels of renin in DCM were positively correlated, and extrapolation of the regression line to normal plasma levels yielded a tissue level close to that measured in the donor hearts. The cardiac tissue-to-plasma concentration (T/P) ratios for renin and prorenin were threefold the ratio for albumin, which indicates that the tissue levels were too high to be accounted for by admixture with blood and diffusion into the interstitial fluid. Cell membranes from porcine cardiac tissue bound porcine renin with high affinity. The T/P ratio for ACE, which is membrane bound, was fivefold the ratio for albumin. Cardiac angiotensinogen was lower in DCM patients than in the donors, and its T/P ratio was half that for albumin, which is compatible with substrate consumption by cardiac renin.
Conclusions These data in patients with heart failure support the concept of local angiotensin production in the heart by renin that is taken up from the circulation. Membrane binding may be part of the uptake process.
Key Words: angiotensin • renin • heart failure
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Introduction |
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The RAS plays an important role in the regulation of blood pressure and salt and fluid homeostasis. The kidney releases both renin and its inactive precursor prorenin into the circulation. Liver-derived angiotensinogen is cleaved in the circulating blood by renin to form Ang I, which is then converted by ACE, located on the luminal side of the vascular endothelium, into Ang II, a potent vasoconstrictor and stimulant of the release of aldosterone.
Agents that interfere with Ang II formation, the ACE inhibitors in particular, are now widely used for the treatment of hypertension and heart failure. Clinical studies indicate that the beneficial effects of ACE inhibitor treatment in heart failure and left ventricular hypertrophy are not solely determined by the effect of ACE inhibition on systemic arterial pressure.1 2 It is, therefore, postulated that these beneficial responses are independent, at least partly, of the effects of ACE inhibition on the circulating RAS.
There is growing evidence to suggest that in cardiac tissue, Ang II is produced locally and does not originate from circulating Ang I.3 4 However, whether the cardiac Ang I and II production depends on renin from the kidney remains a matter of dispute. In normal cardiac tissue of mice and rats, renin mRNA levels are undetectable or extremely low.5 6 In support of this finding is the fact that after bilateral nephrectomy in the pig, cardiac renin, Ang I, and Ang II decrease to levels at or below the detection limit4 ; the same is true for cardiac Ang I and II in the rat.7 Renin expression, however, may be induced under pathological conditions. Renin mRNA can be detected in rat ventricle after myocardial infarction8 and in rat atrium after low-sodium diet and treatment with the ACE inhibitor enalapril.9
Angiotensinogen and ACE mRNAs have been detected in normal cardiac tissue.10 11 12 13 Angiotensinogen mRNA is increased during postinfarction ventricular remodeling in the rat,11 and ACE mRNA is increased during pressure overload–induced ventricular hypertrophy in the rat12 and heart failure in humans.13 Increased levels of ACE activity have been found in left ventricular aneurysms of patients after myocardial infarction.14
In the present study, we measured the tissue levels of prorenin, renin, angiotensinogen, and ACE in normal and failing human hearts. We compared the tissue levels of these RAS components with the levels in simultaneously obtained plasma to address the possibility of cardiac angiotensin formation independent of kidney-derived renin. The possibility of sequestration of circulating renin by cardiac tissue through binding to cardiac cell membranes was investigated in renin-binding studies with the use of cardiac membranes from freshly obtained porcine hearts.
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Methods |
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Collection of Cardiac Tissue and Blood Samples
Left ventricular tissue was obtained from 10 subjects (9 men and 1 woman; age, 30 to 64 years) with end-stage DCM (origin: ischemic heart disease, 7; idiopathic, 2; Becker muscular dystrophy, 1) undergoing cardiac transplantation and from 10 subjects (5 men and 5 women; age, 3 to 54 years) who had died from noncardiac causes (cerebrovascular accident, 4; polytrauma, 4; brain tumor, 2) <24 hours before the tissue arrived in the laboratory. The heart donors were not on cardiovascular medication. The medication of one subject with end-stage DCM could not be retraced. Of the remaining 9 subjects, 9 were receiving a diuretic; 8, an ACE inhibitor (captopril, 5 [average dose, 56.25 mg/d]; enalapril, 3 [average dose, 10 mg/d]); 6, a positive inotropic drug; 3, an antiarrhythmic drug; 2, isosorbide dinitrate 1, nifedipine; and 1, hydralazine.
The donor hearts were provided by the Rotterdam Heart Valve Bank (Bio Implant Services Foundation/Eurotransplant Foundation) after removal of the aortic and pulmonary valves for homograft valve transplantation. The hearts had been taken out of the body immediately after circulatory arrest and maintained at 0° to 4°C in a sterile organ-protecting solution (University of Wisconsin, EuroCollins, or HTK-Bretschneider solution).15 After arrival in the laboratory, a 5- to 10-g piece of left ventricular free wall was dissected from the heart and stored at -70°C. Pieces of left ventricular free wall (3 to 5 g) taken from the failing hearts were frozen in liquid nitrogen and also stored at -70°C immediately after the heart had been removed from the body. Blood was obtained from 6 cardiac transplant recipients at the time of transplantation. Blood samples were collected into polystyrene tubes containing trisodium citrate (final concentration in blood, 0.013 mol/L) and centrifuged at 3000g for 10 minutes at room temperature. Plasma was stored at -70°C and assayed within 1 month.
Frozen cardiac tissue (
1 g) was rapidly minced into small pieces and
homogenized (1:2 [wt/vol]) in 0.01 mol/L phosphate
buffer, pH 7.4, containing 0.15 mol/L NaCl, with a Polytron PT10/35
(Kinematica).4 The cardiac tissue homogenates
were stored at -20°C and assayed within 1 week.
Measurements of Renin and Prorenin
Renin in plasma was quantified by measuring Ang I generation at
pH 7.4 during incubation at 37°C with a saturating concentration of
sheep angiotensinogen in the presence of
angiotensinase, ACE, and serine protease
inhibitors (routine enzyme kinetic assay). Ang I generation
under these conditions is linear for 
3 hours, and the recovery of Ang
I added to plasma before the incubation step at 37°C is
98%.16 Due to the presence of high
angiotensinase activity in cardiac tissue
homogenates, Ang I generation cannot be measured by the
routine enzyme kinetic assay in these homogenates, despite
the addition of angiotensinase
inhibitors.4 Thus, to reliably measure Ang
I–generating activity in cardiac tissue homogenates, the
angiotensinases must be removed (eg, through an
acidification step)4 16 or the breakdown of Ang I must be
prevented by rapidly binding it to an Ang I antibody (antibody-trapping
enzyme kinetic assay).4 17 Because acidification also
leads to activation of prorenin,4 18 we used the
antibody-trapping enzyme kinetic method to measure renin in the cardiac
tissue homogenates. With this assay, we found Ang I
generation at 37°C to be linear for 30 minutes. In addition, the
recovery of [Ile5]Ang I added to cardiac tissue
homogenates before incubation at 37°C was >75% (n=4).
Results of the routine enzyme kinetic and antibody-trapping assays show
good agreement.4
Prorenin was first converted into renin (activation) and then measured with the routine enzyme kinetic assay. Prorenin in plasma was activated with Sepharose-bound trypsin.16 Based on our experience with the activation of prorenin in tissues,4 19 we tested two different procedures to convert cardiac prorenin into renin (ie, acidification only or acidification followed by treatment with plasmin at neutral pH). Tissue homogenate was acidified through dialysis at 4°C for 48 hours against 0.05 mol/L glycine buffer, pH 3.3, containing 0.001 mol/L disodium EDTA and 0.095 mol/L NaCl. This was followed by (1) dialysis at 4°C for 24 hours against 0.1 mol/L phosphate buffer, pH 7.4, containing 0.001 mol/L disodium EDTA and 0.075 mol/L NaCl or (2) quick adjustment of pH to 7.4 with 1 mol/L NaOH and the subsequent addition of 0.2 vol of a solution of human plasmin (final concentration, 1 casein unit/mL) in 0.15 mol/L NaCl and incubation at 4°C for 48 hours.4 18 The acidification step in the two procedures effectively removed the angiotensinase activity; the recovery of [Ile5]Ang I added to cardiac tissue homogenate at pH 7.4, after acid treatment or acid-and-plasmin treatment, was >95% in the routine enzyme kinetic assay (n=4).
Acid treatment of cardiac tissue homogenate followed by restoration of pH to 7.4 and treatment with plasmin led to virtually complete activation of prorenin, as was demonstrated by the >90% conversion and recovery of human recombinant prorenin (a gift of Dr W. Fischli, Hoffmann–La Roche, Basel, Switzerland)4 that was added to the homogenates before the activation step (n=3). Acid treatment followed by restoration of pH to 7.4 without subsequent plasmin treatment led to less complete activation of prorenin; the recovery of added prorenin, measured as renin, was 65% to 78% (n=3). The cardiac tissue homogenates were therefore activated by the combined acid-and-plasmin method.
All samples were assessed in duplicate. Results are expressed as µU/mL or µU/g with the use of the international human kidney renin standard MRC 68/356 (Medical Research Council, National Institute of Biological Standards and Control, London, UK) as a reference. The normal range in plasma is 8 to 55 µU/mL for renin and 88 to 390 µU/mL for prorenin.20
Identification of Cardiac Ang I–Generating Activity as
Renin
Part of the Ang I–generating activity of cardiac tissue
homogenates may be related to the presence of pseudorenin
(eg, cathepsin D).21 To distinguish true renin from
pseudorenin, we used the specific renin inhibitor
remikiren, which has an IC50 value of
7x10-10 mol/L for human renin and
3.5x10-5 mol/L for bovine cathepsin
D.22 Percent inhibition of Ang I–generating activity was
determined at inhibitor concentrations ranging from
10-11 to 10-5 mol/L.
The inhibition curves for cardiac tissue homogenates were
compared with those for plasma and the human kidney renin standard MRC
68/356.
We also used monoclonal renin antibodies to identify Ang I–generating activity as true renin. For this purpose, renin was measured with a sandwich immunoradiometric assay.20 Monoclonal antibody R 3-36-16,23 which reacts equally well with renin and prorenin, was biotinylated and served as a primary antibody in the assay.24 Monoclonal antibody R 1-20-5,25 which reacts with renin but not with prorenin, was labeled with 125I (specific activity, 740 kBEq/µg) and served as the secondary antibody. The results of this assay were expressed as µU/g, with the human kidney renin standard MRC 68/356 as a reference.
Binding of Renin to Cardiac Membranes
Cardiac membranes were prepared from freshly obtained porcine
left ventricular tissue (20 g) as previously
described.4 The membrane fraction contained both plasma
and sarcoplasmic reticulum membranes. Semipurified kidney renin was
prepared from porcine kidney.4 Twenty-five µL of the
cardiac membrane fraction, containing 125 µg protein, was
incubated in a shaking water bath at 37°C and pH 7.4 for 2 hours with
250 µL semipurified porcine kidney renin at six different
concentrations (20 to 400 pmol Ang I/min per mL). Nonspecific binding
was measured by incubating renin with membranes that had been heated
for 10 minutes at 95°C. The incubation was terminated by the addition
of 3 mL of ice-cold 0.01 mol/L phosphate buffer, pH 7.4, containing
0.15 mol/L NaCl, followed by rapid vacuum filtration through a Whatman
GF/B filter. Filters were washed four times with 3 mL phosphate buffer
and incubated with sheep angiotensinogen to measure renin
according to the routine enzyme kinetic assay. The dissociation
constant (Kd) and the maximum number of binding
sites (Bmax) were calculated from plots
according to Scatchard.26
Measurements of Angiotensinogen, ACE, and Serum
Albumin
Angiotensinogen was measured as the maximum quantity
of Ang I that was generated during incubation at pH 7.4 and 37°C with
a high concentration of human kidney renin (10 mU/mL) in the presence
of inhibitors of ACE and
angiotensinases.27 The normal range in plasma
is 745 to 2340 pmol/mL.27 28
ACE was measured with a commercial kit (ACE Color, Fujirebio; normal range, 7 to 20 mU/mL).29
Serum albumin was measured with single radial immunodiffusion (LC and NOR Partigen plates, Behringwerke) according to the method of Mancini et al.30 The normal range is 22 to 43 mg/mL.28
Statistical Analysis
Differences between cardiac transplant recipients and donors
were evaluated for statistical significance by using Student's
t test or Mann-Whitney's U test for unpaired
observations. Statistical significance was accepted at
P<.05.
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Results |
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Levels of Renin, Prorenin, Angiotensinogen, and ACE in Cardiac Tissue
The specific renin inhibitor remikiren, at concentrations of
10-8 mol/L, caused
virtually complete inhibition of the Ang I–generating activity in the
acid-and-plasmin–treated cardiac tissue homogenates (Fig 1
). The inhibition curve (relating the degree of
inhibition to the inhibitor concentration) for cardiac
tissue homogenate treated with acid followed by plasmin was
identical to the curves for untreated plasma and the human kidney renin
standard, which supports the assumption that the measured Ang
I–generating activity of cardiac tissue homogenate is a
valid estimate of true renin. The IC50 value was
3x10-10 mol/L, which is in accordance with
reports in the literature.22 The inhibition curve for
untreated cardiac tissue homogenate differed somewhat from
the inhibition curves for plasma renin and kidney renin (Fig 1); the
difference can be accounted for by assuming that 30% of the Ang
I–generating activity in untreated cardiac homogenate was
caused by pseudorenin. We therefore measured true renin in untreated
cardiac tissue homogenates as the difference between the
Ang I–generating activity in the absence of remikiren and the Ang
I–generating activity in the presence of 10-5
mol/L remikiren.
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), Untreated cardiac tissue
homogenate; (
), cardiac tissue homogenate
pretreated with acid and plasmin; (
), human kidney renin standard
MRC 68/356; and (
), plasma.
Comparison between the results of the enzyme kinetic and
immunoradiometric assays of renin in cardiac tissue
homogenate and plasma from 5 subjects with DCM showed good
agreement (Fig 2), confirming that the enzyme kinetic
assay is indeed a valid measurement of true renin. According to the
enzyme kinetic assay, the plasma concentration of naturally occurring
renin in subjects with DCM was 80±23% (mean±SD) of the renin
concentration after prorenin activation compared with 65±33%
according to the immunoradiometric assay (difference not significant).
The cardiac tissue concentration of naturally occurring renin in these
subjects was 59±19% of the renin concentration after prorenin
activation in the enzyme kinetic assay and 77±11% in the
immunoradiometric assay (difference not significant).
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) before (
Fig 3 is a comparison of the cardiac tissue levels of
renin, prorenin, angiotensinogen, ACE, and serum
albumin between the DCM patients and the donors. The levels of
renin and prorenin were more than fivefold higher in the patients,
whereas angiotensinogen was lower. Cardiac ACE was not
different between the two groups. The cardiac tissue level of serum
albumin was somewhat higher in the DCM patients than in the
donors.
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Plasma levels at the time of heart transplantation were available for 6 of the 10 DCM cases. Plasma renin in these subjects ranged from 472 to 3028 µU/mL, which is more than sevenfold the normal level. Plasma prorenin ranged from 180 to 1214 µU/mL, and in 3 subjects it was above normal. Plasma angiotensinogen ranged from 77 to 484 pmol/mL, which is below the normal range. Plasma ACE ranged from 5.8 to 28.9 mU/mL, and in 3 subjects it was above normal. Albumin in plasma was normal; it ranged from 22 to 34 mg/mL.
The cardiac tissue-to-plasma concentration ratio for serum
albumin was 12% (Fig 4), which is in
agreement with the fact that the localization of this protein is
restricted to the extracellular fluid. Albumin (molecular mass,
70 kD) is known to be present in the interstitial
fluid, albeit in lower concentrations than in plasma.31
The cardiac tissue-to-plasma concentration ratio for
angiotensinogen (molecular mass, 65 kD) was 6%, which is
in keeping with the contention that cardiac angiotensinogen
is also localized in the extracellular fluid. The lower ratio for
angiotensinogen than for albumin may suggest that
the angiotensinogen consumption rate, and therefore the Ang
I production rate, is higher in cardiac tissue than in
circulating plasma. The cardiac tissue levels of renin and
angiotensinogen were negatively correlated (Fig 5), most likely because increased renin leads to
increased substrate consumption. The cardiac tissue-to-plasma ratio for
ACE was 54%, which was much higher than the ratio for serum
albumin. Most of the ACE in cardiac tissue is probably cell
membrane bound.4 The cardiac tissue-to-plasma
concentration ratios for renin and prorenin (molecular mass, 48 and 54
kD, respectively) were 30% and 36%, which was also higher than the
ratio for serum albumin. This suggests that the localization of
these proteins is not restricted to the extracellular fluid
compartment.
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The cardiac tissue levels of renin in the subjects with DCM were directly correlated with the plasma levels of renin (log [cardiac renin]=0.50xlog [plasma renin]+0.93; r=.84, P<.05). There was no significant correlation between the prorenin levels in cardiac tissue and plasma.
Binding of Renin to Cardiac Membranes
Cardiac membranes prepared from porcine left
ventricular tissue (n=8) bound porcine renin in a
dose-dependent way (Fig 6). Binding was maximal within
15 minutes. According to Scatchard analysis,
Kd was 0.21±0.11 nmol Ang I/min per mL and
Bmax was 0.5±0.3 pmol Ang I/min per mg protein.
One nanomole of pure porcine renin generates during incubation at
37°C with saturating concentrations of porcine
angiotensinogen 200 nmol Ang I/min.32 33
With our semipurified preparation of porcine kidney renin, we found the
maximum reaction velocity (Vmax) when incubated
with sheep angiotensinogen to be similar to the
Vmax when incubated with
angiotensinogen prepared from nephrectomized
pigs.34 Thus, Kd was
10-9 mol/L, and Bmax
was 2 fmol/mg protein.
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The results of the present study demonstrate the presence of increased concentrations of renin and prorenin in left ventricular tissue from patients with DCM. The cardiac levels of renin and prorenin were more than fivefold the cardiac levels in the donors. In addition, the cardiac tissue-to-plasma concentration ratios for renin and prorenin (molecular mass, 48 and 54 kD, respectively) were approximately threefold the ratio for serum albumin (molecular mass, 70 kD), indicating that the levels of renin and prorenin in cardiac tissue were too high to be explained by admixture with blood or by diffusion from the blood into the interstitial fluid. In normal porcine left ventricular tissue, the renin level was also higher than can be explained by its localization in extracellular fluid.4
Purified membrane fractions prepared from porcine left ventricular tissue contained renin,4 and specific binding of renin and prorenin to rat renal and other tissue membranes has been reported.35 36 In the present study, we observed high-affinity binding of porcine renin to porcine cardiac membranes. Because the membrane fraction contained both plasma membranes and sarcoplasmic reticulum, it is unclear whether renin binding was specific for plasma membranes. Chemical cross-linking studies also suggest the presence of renin-binding proteins in rat vascular tissue membranes.37 Our findings in the human heart, which indicate that renin and prorenin in cardiac tissue are not restricted to the extracellular fluid, may therefore be explained by binding to cell membranes.
ACE, which is known to be a membrane-bound enzyme, was also found in cardiac tissue in concentrations that were higher than could be explained by its presence in the extracellular fluid. Cardiac ACE levels did not differ between the DCM patients and the donors. It should be noted, however, that 8 of the 10 patients with DCM were receiving ACE inhibitor treatment at the time of cardiac transplantation. This may have led to some underestimation of ACE activity in these patients. In normal hearts, ACE appears to be limited to the vascular endothelium and the endocardium.38 39 After myocardial infarction in humans, ACE can also be detected in the remaining viable cardiomyocytes near the infarct scar of the aneurysmal left ventricle,38 as well as in fibroblasts, vascular smooth muscle cells, and macrophages in the scar area itself.38 After coronary occlusion in rats, ACE was demonstrated in fibroblasts in the healthy hypertrophying part of the heart.40
The patients with DCM had markedly increased levels of renin and reduced levels of angiotensinogen in circulating plasma at the time of transplantation. These are characteristic findings in patients with end-stage heart failure who are treated with diuretics and ACE inhibitors.41 42 The cardiac level of angiotensinogen in these patients was approximately one third of the level in the donors and was negatively correlated with the renin concentration. This is probably related to the fact that substrate consumption is increased when renin is increased. An interesting finding was that the cardiac tissue-to-plasma concentration ratio for angiotensinogen (molecular mass, 65 kD) was half the ratio for albumin (molecular mass, 70 kD). This is evidence in favor of consumption of angiotensinogen that is present in the cardiac extracellular fluid through the reaction with renin, thereby implying that local Ang I production occurs in the heart.
In the DCM patients in whom measurements of renin were available in cardiac tissue as well as in plasma, the tissue and plasma levels showed a positive correlation. Extrapolation of the regression line to normal plasma concentrations yielded a tissue concentration of renin close to the concentration measured in the donor hearts. Thus, there was no evidence to suggest that the regulation of cardiac renin is independent of the regulation of circulating renin. A previous study by our group of the effect of nephrectomy on the cardiac levels of renin in healthy pigs showed that most, if not all, renin in cardiac tissue originates from the kidney.4 Studies in which intravenous bolus injections of radiolabeled renin were given to rats and monkeys have demonstrated that the enzyme accumulated in the heart.43 44
Prorenin in cardiac tissue was not significantly correlated with prorenin in plasma. It should be noted, however, that the measurement of prorenin is not as accurate as the measurement of renin. Renin was measured as the Ang I–generating activity without prior in vitro activation of prorenin, whereas prorenin was measured as the difference between the Ang I–generating activity after prorenin activation and the Ang I–generating activity before activation. The results of this subtraction method are sufficiently accurate when renin is low compared with prorenin, as is the case in normal plasma. Results are less accurate when the renin-to-prorenin ratio is higher, as was the case in both plasma and cardiac tissue in the patients with DCM. Another explanation for the apparent lack of a correlation between the measured levels of prorenin in cardiac tissue and plasma might be that part of the plasma-derived prorenin is activated in cardiac tissue. Such in vivo activation of plasma-derived prorenin in extrarenal tissues, however, has never been demonstrated.
In addition to the evidence presented here, there is growing evidence from the literature to support the existence of local angiotensin formation in cardiac tissue. Perfusion of the isolated rat heart with renin leads to Ang I and II release into the coronary effluent3 and to Ang I release into the interstitial fluid.45 Without the addition of renin to the perfusion fluid, the cardiac release of Ang I and II was practically zero. The study reported here provides no data on Ang I and II levels in cardiac tissue and plasma. Special precautions are required when samples for measuring these peptides are collected, and these precautions could not always be taken in the setting of this study. It appears logical to assume that the elevated renin concentrations in the hearts affected by DCM will promote cardiac Ang I and II production. Experiments in intact pigs showing reduced cardiac contractility in response to intracoronary administration of the renin inhibitor remikiren support the fact that cardiac Ang II production has functional significance46 ; the time course of this response was not correlated with the effects of the inhibitor on the levels of Ang I and II in the circulation. Intracardiac Ang I and II production may also participate in the long-term processes of hypertrophy and remodeling after myocardial infarction.47
In summary, our results add to the growing evidence in support of local Ang I and II production by the heart. So far, attempts to show that the production of these peptides is independent of renin from the circulation have failed, at least in normal hearts. The present study also fails to provide such evidence in DCM patients with severe heart failure; rather, our results are in keeping with the contention that renin from the circulation is taken up by the heart and that tissue binding of renin is part of the uptake process.
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Selected Abbreviations and Acronyms |
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Received September 16, 1996; revision received January 24, 1997; accepted February 2, 1997.
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