ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice
There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pressure overload by transverse aortic constriction (TAC). For the next 7 days the groups received either the specific angiotensin II subtype 1 receptor (AT1) antagonist (losartan, 1.05 g/l; n = 17), an angiotensin enzyme inhibitor (captopril, 2 g/l; n = 17), or no treatment (n = 22) administered in the drinking water and compared with three similarly treated sham-operated groups (n = 7 each). TAC resulted in a significant increase in heart weight-to-body weight ratio (0.634 ± 0.087 vs. 0.525 ± 0.039, g/g x 100, P < 0.05), which was prevented by losartan (0.506 ± 0.069, g/g x 100, P < 0.0001) despite similar hemodynamic load (proximal systolic pressure 146 ± 31 vs. 136 ± 32 mmHg, untreated vs. losartan, P = NS). Proximal systolic pressure was positively correlated with the development of ventricular hypertrophy. In the presence of AT1-receptor blockade, the increase in heart weight-to-body weight ratio at any given systolic pressure was significantly attenuated compared with untreated TAC mice. The increase in heart weight-to-body weight ratio was also significantly attenuated by captopril compared with untreated banded controls (0.542 ± 0.091, g/g x 100, P = 0.01). To assess whether AT1-receptor blockade could alter transcriptional activation of the atrial natriurtic factor (ANF) gene, Northern blot analysis was performed in losartan and untreated TAC animals. Matched for hemodynamic load, AT1-receptor blockade significantly inhibited the upregulation in ANF gene expression. We conclude that angiotensin II plays an important role in the induction of pressure- overload hypertrophy and that the prominent pathway for the conversion of angiotensin I to angiotensin II is converting-enzyme dependent in this murine model. The marked inhibition of ANF gene expression upregulation suggests that transcriptional activation for one of the genes of the hypertrophic gene program is in part dependent on the presence of angiotensin II and not on mechanical activation alone.
Rockman, HA; Wachhorst, SP; Mao, L; Ross, J
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