Syndecan-1: 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)-β signaling pathways.2 Angiotensin II upregulates TGF-β …