Regulation of cardiac collagen: angiotensin and cross-talk with local growth factors.

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In the myocardium, collagen fibers provide a supporting framework for myocytes and blood vessels and act as lateral connections between muscle bundles. These functional properties of collagen serve to maintain tissue architecture and to coordinate the delivery of force generated by myocytes on the ventricular chamber. The accumulation of excess collagen is believed to be an important pathophysiological process that contributes to diastolic heart failure. Diastolic heart failure accounts for 30% to 50% of heart failure in clinical practice, and hypertensive disease is the major cause of this type of heart failure.1 The precise mechanisms responsible for excess fibrillar collagen accumulation in the pathological heart are poorly understood. Fibrosis of both the injured and noninjured myocardium2 indicates that humoral mechanisms are responsible for this process. In the failing heart, several humoral, autocrine, and paracrine systems are activated,3 suggesting that cross-talk between synergistic and opposing signaling pathways constitutes the predominant form of regulation under these conditions. Several factors have been identified as potentially important mediators of cardiac collagen production. In vitro studies of neonatal and adult rat cardiac fibroblasts have shown that angiotensin II (Ang II) directly stimulates cardiac fibroblast proliferation and collagen synthesis via Ang II type 1 (AT1) receptors.4 5 6 In this issue of Hypertension , Pathak et al7 provided evidence that a myocyte cofactor was an important mediator of Ang II–induced collagen type I and type III mRNA synthesis in a rat cell coculture model. This work, together with other studies, provides strong evidence that Ang II indirectly regulates cardiac fibroblast function via specific growth factors.8 9 10 11 12 13 14 15 16 17 18 19 20 21 Although the primary autocrine and paracrine mediators of Ang II effects on fibrillar collagen synthesis remain to be elucidated, principal candidates …