The role of the renin-angiotensin system in cardiovascular remodeling.

摘要

There is increasing evidence that the renin-angiotensin system (RAS) may play a critical role in the development of the left ventricular hypertrophy (LVH), coronary artery medial wall thickening, and perivascular fibrosis (cardiovascular remodeling). The studies in this dissertation were designed to determine the role of the RAS, specifically angiotensin II (Ang II), in cardiovascular remodeling. The first study tested the hypothesis that the angiotensin converting enzyme (ACE) inhibitor, captopril, would prevent cardiovascular remodeling in a rat model of hypertension. Captopril attenuated the increase in minimal coronary resistance, coronary artery medial wall thickening, and the increase in perivascular fibrosis, but it had no effect on LVH. This study suggested that LVH was pressure dependent while the other aspects of cardiovascular remodeling were mediated by the RAS. The second study sought to determine whether the development of cardiovascular remodeling could be attenuated by specifically inhibiting the actions of Ang II. Similar to the previous study, this study suggested that arterial pressure mediated LVH while coronary medial wall thickening and perivascular fibrosis were mediated by Ang II. To determine if there was altered expression of the Ang II receptor in normotensive vs hypertensive rats, Ang II receptor expression in cardiac fibroblasts from normotensive and spontaneously hypertensive rats (SHR) was examined. It was found that cardiac fibroblasts isolated from SHR expressed significantly more Ang II receptors than those isolated from normotensive rats, suggesting that the increased Ang II receptor levels from SHR cardiac fibroblasts may play a role in the increased myocardial fibrosis seen in this model. To further investigate the role of the RAS on the initiation of vascular hypertrophy, the heart and vasculature of 8-10 month-old SHR that were either left untreated, given captopril throughout life, or given captopril from in utero to two months of age were examined. This study showed that lifetime treatment as well as early, short-term treatment of SHR with captopril prevented LVH and intramyocardial artery wall thickening, suggesting that the RAS, early in development, may play a critical role in cardiovascular remodeling. The results presented in these studies suggest that while arterial pressure is the main mediator of LVH, Ang II plays a critical role in the development of coronary arterial wall thickening and perivascular fibrosis.