title: Pharmacological modulation of cardiac fibroblast function.
abstract: The cardiac interstitium is composed of nonmyocyte cells and a structural protein network which plays a dominant role in governing the structure, architecture, and mechanical behavior of the myocardium. The heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for myocardial collagen metabolism and fibrous tissue accumulation, may largely explain the appearance of diastolic and/or systolic myocardial failure. Regulatory mechanisms that are related to the fibrous tissue response in various cardiovascular diseases, e.g., hypertensive heart disease, dilated cardiomyopathy or post myocardial infarction, are of primary clinical interest. A better understanding of the hitherto neglected role of cardiac fibroblasts in mediating an adverse structural remodeling of the myocardium will lead to specific pharmacologic agents that interfere with the fibrous tissue response. Several lines of evidence based on in vivo and in vitro studies suggest that circulating and tissue renin-angiotensin-aldosterone systems (RAAS) are involved in the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition or aldosterone receptor antagonism that was found to prevent myocardial fibrosis in the rat with renovascular or genetic hypertension. In cultured adult cardiac fibroblasts, an angiotensin (Ang)II- or aldosterone-mediated dose-dependent increase in collagen synthesis could be completely abolished by the use of AngII type 1 or mineralocorticoid receptor antagonists, respectively. Likewise, the AngII-mediated decrease in the activity of matrix metalloproteinase 1, the key enzyme for interstitial collagen degradation, could be antagonized by AngII receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Molecular Cardiology Lab, Philipps University of Marburg, Germany.
authors.forename: C G
authors.initials: CG
authors.lastname: Brilla
authors.forename: B
authors.initials: B
authors.lastname: Maisch
authors.forename: H
authors.initials: H
authors.lastname: Rupp
authors.forename: R
authors.initials: R
authors.lastname: Funck
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: K T
authors.initials: KT
authors.lastname: Weber
mesh_terms: D000450:Aldosterone / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004719:Endomyocardial Fibrosis / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003094:Collagen; D007703:Peptidyl-Dipeptidase A