INCREASED MESSENGER-RNA EXPRESSION OF CARDIAC RENIN-ANGIOTENSIN SYSTEM AND COLLAGEN-SYNTHESIS IN SPONTANEOUSLY HYPERTENSIVE RATS

Hypertensive cardiac hypertrophy is associated with the accumulation o f collagen in the myocardial interstitium. Previous studies have demon strated that this myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction. Although cardiac fibroblasts a re responsible for the synthesis of fibrillar collagen, the factors th at regulate collagen synthesis in cardiac fibroblasts are not fully un derstood. We investigated the effects of angiotensin II on cardiac col lagen synthesis in cardiac fibroblasts. Cardiac fibroblasts of 10 week old spontaneously hypertensive rats and age-matched Wistar-Kyoto rats were prepared and maintained in culture medium supplemented with 10% fetal calf serum. The expression of mRNA of the renin-angiotensin syst em (renin, angiotensinogen, angiotensin converting enzyme) was determi ned by using a ribonuclease protection assay. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6 f old greater than that in the cell of Wistar-Kyoto rats. Angiotensin II stimulated collagen synthesis in cardiac fibroblasts in a dose-depend ent manner, The responsiveness of collagen production to angiotensin I I was significantly enhanced in cardiac fibroblasts from spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 +/- 18% incr ease above basal levels, 185 +/- 18 versus 128 +/- 19% in Wistar-Kyoto rats p < 0.01). This effect was receptor-specific, because it was blo cked by the competitive inhibitor saralasin and MK 954. These results indicate that collagen production was enhanced in cardiac fibroblasts from spontaneously hypertensive rats, that angiotensin II had a stimul atory effect on collagen synthesis in cardiac fibroblasts, and that ca rdiac fibroblasts from spontaneously hypertensive rats were hyper-resp onsive to stimulation by angiotensin II. Level of angiotensin and reni n mRNA expressed in ventricles, and angiotensinogen mRNA expressed in fibroblasts from SHR were higher than those from WKY. These findings s uggest that the cardiac renin-angiotensin system may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.