Overexpression of angiotensin ll type l receptor in pression of angiotensin ll type l receptor in cardiomvocytes induces cardiac hypertrophy and remodeling

摘要

Angiotensin lI (All) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the All type 1 receptor (AT1R). All has also been implicated in the development of cardiac hypertrophy because angiotensin l-con- verting enzyme inhibitors and AT1 R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of All at cardiac as well as vascular levels. and reduce blood pressure, it has been difficult to determine whether All action on the heart is direct or a consequence of pressure-overload. To determine whether All can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1 R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mam- mals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natri- uretic factor and interstitiaI collagen deposition and died prema- turely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for All in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of All in the pathogenesis of cardiac diseases.