Altered signal transduction system in hypertrophiedmyocardium: Angiotensin II stimulates collagen synthesis in hypertrophied hearts

Abstract

Hypertensive cardiac hypertrophy is associated with the accumulation of collagen in the myocardial interstitium. Previous studies have demonstrated that this myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction. Although cardiac fibroblasts are responsible for the synthesis of fibrillar collagen, the factors that regulate collagen synthesis in cardiac fibroblasts are not fully understood. We investigated the effects of angiotensin II on cardiac collagen synthesis in cardiac fibroblasts of 10-week-old spontaneously hypertensive rats and age-matched WKY rats. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6-fold greater than that in the cell of WKY rats. Angiotensin II stimulated collagen synthesis in cardiac fibroblasts in a dose-dependent manner. The responsiveness of collagen production to angiotensin II was significantly enhanced in cardiac fibroblasts from spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 +/- 18% increase above basal levels, 185 +/- 18 vs 128 +/- 19% in WKY rats, P < .01). This effect was receptor-specific, because it was blocked by the competitive inhibitors saralasin and MK 954. These results indicate that collagen production is enhanced in cardiac fibroblasts from spontaneously hypertensive rats, that angiotensin II has a stimulatory effect on collagen synthesis in cardiac fibroblasts, and that cardiac fibroblasts from spontaneously hypertensive rats are hyper-responsive to stimulation by angiotensin II. In the hearts of spontaneously hypertensive rats, mRNA of the renin-angiotensin system (renin, angiotensinogen, angiotensin converting enzyme) was expressed. Levels of angiotensinogen and renin mRNA expressed in ventricles, and angiotensinogen mRNA expressed in fibroblasts from SHR were higher than those from WKY. ACE mRNA was also more strongly expressed in the ventricles and fibroblasts from SHR compared with those of WKY. These findings suggest that the cardiac reninangiotensin system may play an important role in collagen accumulation in hypertensive cardiac hypertrophy (fig.4).