A Critical Mediator in Cardiac Fibrosis

Cardiac fibrosis is characterized by net accumulation of extracellular matrix in the myocardium and is an integral component of most cardiac pathological conditions. Fibrotic remodeling of the ventricle has profound consequences on cardiac function. Increased deposition of interstitial collagen in the perimysial space is initially associated with a stiffer ventricle and diastolic dysfunction. At a later stage, accumulation of extracellular matrix proteins in the cardiac interstitium activates proteolytic pathways leading to the development of ventricular dilation and systolic failure. Disturbance of the matrix network in the fibrotic heart may cause systolic dysfunction through several distinct mechanisms. First, loss of fibrillar collagen may impair transduction of cardiomyocyte contraction into myocardial force development resulting in uncoordinated contraction of cardiomyocyte bundles. Second, disruption of key interactions between endomysial matrix proteins (eg, laminin and collagen) and their receptors in cardiomyocytes may promote cardiomyocyte death.1 Finally, fibrosis may result in sliding displacement (slippage) of cardiomyocytes leading to a decrease in the number of muscular layers in the ventricular wall and subsequent left ventricular dilation. Beyond its effects on cardiac function, fibrotic ventricular remodeling also promotes arrhythmogenesis through impaired anisotropic conduction and subsequent generation of reentry circuits. Extensive evidence suggests that hemodynamic overload activates the renin-angiotensin system triggering potent fibrogenic signals that stimulate cardiac fibroblasts and enhance collagen deposition in the myocardium. Angiotensin II, the central effector molecule of the renin-angiotensin system, stimulates fibroblast proliferation and promotes matrix protein synthesis through interactions involving the angiotensin II type 1 receptor. Angiotensin II–induced fibrosis appears to be mediated, at least in part, through activation of transforming growth factor (TGF)signaling pathways.2 Angiotensin II upregulates TGFsynthesis by cardiac fibroblasts and induces expression of the matricellular protein thrombospondin-1, a crucial activator of latent TGF. Increased levels of bioactive TGFin the cardiac interstitium modulate fibroblast phenotype, promoting collagen synthesis and enhancing matrix preservation through upregulation of tissue inhibitors of metalloproteinases. Active TGFbinds to the constitutively active type II receptor at the cell surface. The complex subsequently interacts with and transphosphorylates the cytoplasmic domain of the type I receptor (T RI). Phosphorylation of the TGFtype I receptor propagates downstream intracellular signals through the Smad proteins, essential components of the TGFsignaling pathway. Activation of the Smad2/3 pathway is crucial for TGF– mediated synthesis of matrix proteins and tissue inhibitors of metalloproteinases by cardiac fibroblasts.3 It is becoming increasingly appreciated that regulation of angiotensin II/TGFsignaling involves interactions with extracellular matrix proteins and proteoglycans. Highlighting the complexity of the molecular circuitry involved in transducing angiotensin II–mediated fibrogenic actions, Schellings et al4 identified the heparan sulfate proteoglycan syndecan-1 as an essential mediator in angiotensin II–induced cardiac fibrosis. Angiotensin II treatment resulted in marked upregulation of syndecan-1 in the mouse heart, predominantly localized in fibrotic areas. Angiotensin II–induced fibrosis and dysfunction were attenuated in syndecan-1 null hearts; the protective effects of syndecan-1 loss were associated with blunted expression of the TGF–inducible gene connective tissue growth factor. Absence of syndecan-1 reduced matrix protein synthesis in angiotensin II–stimulated cardiac fibroblasts; these in vitro effects of syndecan-1 loss were associated with decreased activation of the Smad2 pathway. On the other hand, adenoviral overexpression of syndecan-1 accentuated TGF1– and angiotensin II–mediated Smad2 phosphorylation and enhanced connective tissue growth factor induction, suggesting that syndecan-1 augments responses to fibrogenic mediators. In contrast, fibroblasts treated with recombinant syndecan-1 ectodomain without heparin sulfate groups had no effect on Smad2 phosphorylation and connective tissue growth factor expression, indicating that syndecan-1 heparan sulfates are involved in fibrogenic signal transduction. The findings provide the first demonstration of a role for syndecan-1 in the pathogenesis of cardiac fibrosis. In addition, the study contributes new insights into the significance of proteoglycan-mediated interactions in fibrotic tissue remodeling. A growing body of evidence suggests that, beyond their structural role, proteoglycans are directly involved in regulating cell:cell and cell:matrix interactions. The syndecan family of heparan sulfate proteoglycans is composed of 4 members (syndecan-1 through -4), each consisting of an extracellular domain with covalently attached heparan sulfate or chondroitin sulfate chains, a transmembrane domain, and a short cytoplasmic tail.5 Syndecans act as coreceptors for The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Tex. Correspondence to Nikolaos G. Frangogiannis, Section of Cardiovascular Sciences, 1 Baylor Plaza BCM620, Houston, TX 77030. E-mail [email protected] (Hypertension. 2010;55:00-00.) © 2010 American Heart Association, Inc.