Role of the Renin-Angiotensin System in the Development of Hypertensive Left Ventricular Hypertrophy

Abstract

Previous studies have demonstrated that angiotensin II (AII) acts as a growth-promoting factor on cardiac myocytes and that treatment with angiotensinconverting enzyme (ACE) inhibitors induces reduction of left ventricular mass and suppression of ventricular remodeling. These results suggest that the renin-angiotensin system (RAS) may play an important role in the development of hypertensive left ventricular hypertrophy (LVH). Moreover, it has recently been demonstrated that gene expression of angiotensinogen and ACE is augmented in pressure-overloaded left ventricles, suggesting that endogenous AII produced by the activated cardiac RAS may contribute to the formation of LVH. To elucidate the role of the RAS in the progression of cardiac hypertrophy, we evaluated the effect of the type 1 AII receptor (AT1 receptor) antagonist on LVH in spontaneously hypertensive rats (SHR) and investigated the molecular mechanisms by which antagonism of AII receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretching. In the in vivo study, we treated SHR with a nonpeptide AT1 receptor antagonist, TCV-116. Treatment with TCV-116 reduced anatomical left ventricular (LV) weight, echocardiographic LV wall thickness, transverse diameter of myocytes, and the relative amount of V3 myosin heavy-chain and interstitial collagen volume fraction. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974, an active metabolite of TCV-116. Pretreatment of cultured cardiomyocytes with CV-11974 partially inhibited an increase in MAP kinase activity, c-fos gene expression and [3H] phenylalanine incorporation induced by stretching of cardiomyocytes. These results indicate that (1) the RAS plays a critical role not only in the development of hypertensive LVH but also in the ventricular remodeling associated with LVH, which subsequently leads to the impairment of cardiac function and (2) endogenous AII produced by the cardiac RAS contributes to the pathogenesis of LVH.