| Rats were treated with Ang II, in the presence or absence of Ang-(1-7), to determine the effect of the heptapeptide on Ang II-mediated cardiac myocyte hypertrophy, fibrosis and vascular hypertrophy. Subcutaneous infusion of Ang II (24 microg/kg/h) for 28 days into male Sprague-Dawley rats increased systolic blood pressure (174.7 +/- 6.3 mmHg), compared to saline-infused animals (125.8 +/- 4.5 mmHg, n = 6, p < 0.01) or rats infused with Ang-(1-7) alone (s.c., 24 microg/kg/h for 28 days; 127.4 +/- 3.7, n = 6); however, co-treatment with Ang-(1-7) did not alter the Ang II-induced increase in blood pressure (168.3 +/- 8.3 mmHg). Microscopic evaluation of cardiac myocyte cross-sectional area (MCSA) showed that Ang II significantly increased MCSA (33%) compared to saline-infused controls, while co-infusion of Ang-(1-7) significantly prevented the Ang II-mediated increase in MCSA (p < 0.001). In addition, hearts of animals infused with Ang II showed a marked increase in atrial natriuretic peptide (ANP) mRNA (3.76 +/- 0.53) and brain natiruretic peptide (BNP) mRNA, markers of cardiac hypertrophy, compared to saline-infused animals (1.02 +/- 0.06). Concomitant treatment with Ang-(1-7) significantly attenuated the increase in ANP and BNP mRNA (1.043 +/- 0.11). These data indicate that the heptapeptide attenuates cardiac myocyte hypertrophy in this hypertensive model.;Previous studies demonstrated that stimulation of MAP kinases is associated with cardiac hypertrophy while over-expression of the MAP kinase phosphatase MKP-1 (the dual-specificity phosphatase, DUSP-1) reduced cardiac hypertrophy. Ang-(1-7) significantly increased DUSP-1 protein expression in the heart (2.64 +/- 0.68, n = 6, p < 0.05) compared to animals treated with saline (0.90 +/-.0.30). Co-infusion of Ang II and Ang-(1-7) markedly enhanced the expression of DUSP-1 (3.08 +/- 0.98). The reduction in MAP kinase activity along with the up-regulation of DUSP-1 suggests that the heptapeptide attenuates cardiac myocyte hypertrophy by inhibition of MAP kinase activity associated with increased phosphatase activation.;Ang II infusion increased coronary artery hypertrophy (63.9%) as well as interstitial (54.3%) and perivascular fibrosis (51.4%) compared to saline-treated rats. Co-infusion with Ang-(1-7) reduced both interstitial (1.26 +/- 0.82% compared to 2.76 +/- 0.25% following Ang II treatment, p < 0.001) and perivascular fibrosis (18.60 +/- 1.38% compared to 38.3 +/- 1.95% after Ang II treatment, p < 0.001). The Ang II-mediated increase in vascular hypertrophy was decreased by co-treatment with Ang-(1-7) (21.60%, p < 0.001). These results demonstrate that Ang-(1-7) causes a pressure-independent reduction in cardiac fibrosis and vascular hypertrophy, suggesting that the heptapeptide may be used therapeutically to reduce cardiac remodeling associated with hypertensive heart failure.;Ang II and endothelin-1 (ET-1), key players in the development of cardiac remodeling, stimulate the growth of cardiac fibroblasts to increase fibrosis. Since Ang-(1-7) inhibits mitogen-stimulated cell proliferation, we studied the effect of Ang-(1-7) on ET-1-stimulated growth of neonatal rat cardiac fibroblasts. Treatment of isolated cardiac fibroblasts with Ang-(1-7) attenuated ET-1-stimulated DNA (by 31.5%) and protein synthesis (by 30.9%), as measured by the incorporation of 3H-thymidine and 3H-leucine, respectively, into actively growing cells. The reduction in cardiac fibroblast cell growth with 100 nM Ang-(1-7) treatment was associated with a decrease in ET-1-stimulated phospho-ERK1 (by 64%) and ERK2 (by 59%) and Ang II-stimulated ERK1 (by 72%) and ERK2 (by 83%). Treatment of cardiac fibroblasts with 100 nM Ang-(1-7) for 6 h caused a 4.8 +/- 0.8-fold increase in DUSP-1 mRNA (n = 4, p < 0.05); in contrast, incubation with ET-1 alone had no effect. Collectively, these data suggest that Ang-(1-7) may serve as an effective treatment to reduce cardiac myocyte hypertrophy, cardiac fibrosis and vascular hypertrophy by eliciting anti-proliferative and anti-fibrotic properties and thus may attenuate cardiac remodeling associated with chronic hypertension. (Abstract shortened by UMI.)... |
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