Chronic hypertension induces cardiac remodeling, including left ventricular hypertrophy and fibrosis, through a combination of both hemodynamic and humoral factors. In previous studies, we showed that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] prevented mitogen-stimulated growth of cardiac myocytes in vitro, through a reduction in the activity of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. In this study, saline- or Ang II-infused rats were treated with Ang-(1-7) to determine whether the heptapeptide reduces myocyte hypertrophy in vivo and to identify signaling pathways involved in the process. Ang II infusion into normotensive rats elevated systolic blood pressure >50 mm Hg, in association with increased myocyte cross-sectional area, ventricular atrial natriuretic peptide (ANP) and ventricular brain natriuretric peptide (BNP) mRNAs. Although infusion with Ang-(1-7) had no effect on the Ang II-stimulated elevation in blood pressure, the heptapeptide hormone significantly reduced the Ang II-mediated increase in myocyte cross-sectional area, interstitial fibrosis, and natriuretic peptide mRNAs. Ang II increased phospho-ERK1 and -ERK2, while co-treatment with Ang-(1-7) reduced the phosphorylation of both MAP kinases. Neither Ang II nor Ang-(1-7) altered the ERK1/ERK2 MAP kinase kinase, MEK1/2. However, Ang-(1-7) infusion, with or without Ang II, increased the MAP kinase phosphatase DUSP1; in contrast, treatment with Ang II had no effect on DUSP1, suggesting that Ang-(1-7) up-regulates DUSP1 to reduce Ang II-stimulated ERK activation. These results indicate that Ang-(1-7) attenuates cardiac remodeling associated with a chronic elevation in blood pressure and up-regulation of a MAP kinase phosphatase, and may be cardioprotective in patients with hypertension.
- angiotensin II
- cardiac hypertrophy
- MAP kinase
- Copyright © 2011, American Journal of Physiology - Heart and Circulatory Physiology