In hypertensive heart disease, reactive myocardial fibrosis represents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium. The fact, that the myocardium of both ventricles is involved, irrespective of ventricular loading conditions, suggests that circulating factors, and not the hemodynamic load are primary responsible for this adverse response of the myocardial fibrous tissue. In various experimental in vivo models, it has been shown that myocardial fibrosis is always associated with activation of circulating or local renin-angiotensin-aldosterone systems (RAAS).
Cardiac collagen metabolism is regulated by cardiac fibroblasts which express mRNAs for types I and III collagens, the major fibrillar collagens in the heart, and for interstitial collagenase or matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation.
In order to elucidate the role of the RAAS effector hormones, angiotensin II (AngII) and aldosterone (ALDO), in the regulation of collagen synthesis or inhibition of MMP 1 production, adult human cardiac fibroblasts were cultured. Collagen synthesis was determined by 3H-proline incorporation, and MMP 1 activity by degradation of 14C-collagen measured under serum-free conditions in confluent fibroblasts after 24 hour-incubation with either AngII or ALDO over a wide range of concentrations (10-11–10-6M). In addition, the effects of the mineralocorticoid, deoxycorticosterone (DOC), and prostaglandin E2 (PGE2) on cardiac fibroblast function were determined. Compared with untreated control fibroblasts, collagen synthesis, normalized per total protein synthesis, showed a significant and dose-dependent increase after incubation with either mineralocorticoid hormone, ALDO or DOC, or after incubation with AngII. In contrast, collagen synthesis of cardiac fibroblasts was significantly decreased by PGE2 treatment. Angli type 1 or mineralocorticoid receptor antagonists, respectively, were able to completely inhibit the AngII- or mineralocorticoid-mediated increase of collagen synthesis. Furthermore, AngII significantly decreased MMP 1 activity while ALDO or DOC had no effect on cardiac fibroblast-mediated collagen degradation. In contrast, PGE2 significantly increased MMP 1 activity.
Thus cardiac fibroblast function is modulated by either effector hormone of the RAAS, AngII and ALDO, via specific receptors that lead to progressive myocardial fibrosis in disease states where circulating or local RAAS is activated, i.e., in hypertensive heart disease. In contrast, PGE2, which would be elevated in myocardial tissue after angiotensin-converting enzyme inhibition, counteracts the fibrotic effects of the RAAS on myocardial tissue.
Weber KT, Brilla CG (1991) Pathological hypertrophy and cardiac interstitium: fibrosis and reninangiotensin-aldosterone system. Circulation 83:1849–1865PubMedCrossRefGoogle Scholar
Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT (1990) Remodeling of the rat right and left ventricle in experimental hypertension. Circ Res 67:1355–1364PubMedCrossRefGoogle Scholar
Weber KT (1989) Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 13:1637–1652PubMedCrossRefGoogle Scholar
Factor SM, Robinson TF (1988) Comparative connective tissue structure — function relationships in biologic pumps. Lab Invest 58:150–156PubMedGoogle Scholar
Caulfield JB, Borg TK (1979) The collagen network of the heart. Lab Invest 40:364–372PubMedGoogle Scholar
Factor SM, Zhao MJ, Eng C, Robinson TF (1988) The effects of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue. J Am Coll Cardiol 12:1582–1589PubMedCrossRefGoogle Scholar
Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI (1988) Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 62:757–765PubMedCrossRefGoogle Scholar
Chapman D, Weber KT, Eghbali M (1990) Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in hypertrophied rat myocardium. Circ Res 67:787–794PubMedCrossRefGoogle Scholar
Lindy S, Turto H, Uitto J (1972) Protocollagen proline hydroxylase activity in rat heart during experimental cardiac hypertrophy. Circ Res 30:205–209PubMedCrossRefGoogle Scholar
Morkin E, Ashford TP (1968) Myocardial DNA synthesis in experimental cardiac hypertrophy. Am J Physiol 215:1409–1413PubMedGoogle Scholar
Doering CW, Jalil JE, Janicki JS, Pick R, Aghili S, Abrahams C, Weber KT (1988) Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res 22:686–695PubMedCrossRefGoogle Scholar
Jalil JE, Janicki JS, Pick R, Shroff SG, Weber KT (1989) Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64:1041–1050PubMedCrossRefGoogle Scholar
Silver MA, Pick R, Brilla CG, Jalil JE, Janicki JS, Weber KT (1990) Reactive and reparative fibrosis in the hypertrophied rat left ventricle: Two experimental models of myocardial fibrosis. Cardiovasc Res 24:741–747PubMedCrossRefGoogle Scholar
Brilla CG, Weber KT (1992) Reactive and reparative myocardial fibrosis in arterial hypertension. Cardiovasc Res 26:671–677PubMedCrossRefGoogle Scholar
Weber KT, Janicki JS, Pick R, Capasso J, Anversa P ( 1990) Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am J Cardiol 65:1G-7GCrossRefGoogle Scholar
Jalil JE, Janicki JS, Pick R, Abrahams C, Weber KT (1989) Fibrosis-induced reduction of endomyocardium in the rat after isoproterenol treatment. Circ Res 65:258–264PubMedCrossRefGoogle Scholar
Capasso JM, Palackal T, Olivetti G, Anversa P (1990) Left ventricular failure induced by long term hypertension in rats. Circ Res 66:1400–1412PubMedCrossRefGoogle Scholar
Jalil JE, Janicki JS, Pick R, Weber KT ( 1991 ) Coronary vascular remodeling and myocardial fibrosis in the rat with renovascular hypertension: response to Captopril. Am J Hypertens 4:51–55PubMedGoogle Scholar
Brilla CG, Matsubara LS, Weber KT (1993) Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 25:563–575PubMedCrossRefGoogle Scholar
Weber KT, Pick R, Silver MA, Moe GW, Janicki JS, Zucker IH, Armstrong PW (1990) Fibrillar collagen and the remodeling of the dilated canine left ventricle. Circulation 82:1387–1401PubMedCrossRefGoogle Scholar
Berg RA, Moss J, Baum BJ, Crystal RG (1981) Regulation of collagen production by the β-adrenergic system. J Clin Invest 67:1457–1462PubMedCrossRefGoogle Scholar
Fine A, Goldstein RH (1987) The effect of PGE2 on the activation of quiescent lung fibroblasts. Prostaglandins 33:903–913PubMedGoogle Scholar
Goldstein RH, Poliks CF, Pilch PF, Smith BD, Fine A (1989) Stimulation of collagen formation by insulin and insulin-like growth factor 1 in cultures of human lung fibroblasts. Endocrinology 124:964–970PubMedCrossRefGoogle Scholar
Fine A, Goldstein RH (1987) The effect of transforming growth factor-β on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem 262:3897–3902PubMedGoogle Scholar
Brilla CG, Zhou G, Matsubara L, Weber KT (1994) Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol 26:809–820PubMedCrossRefGoogle Scholar
Villareal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH (1993) Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88:2849–2861CrossRefGoogle Scholar
Rana RS, Hokin LE (1990) Role of phosphoinositides in transmembrane signaling. Physiol Rev 70:115–164PubMedGoogle Scholar
Brilla CG, Scheer C, Rupp H (1997) Renin-angiotensin system and myocardial collagen matrix: modulation of cardiac fibroblast function by angiotensin II type 1 receptor antagonism. J Hypertens: in pressGoogle Scholar