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The Role of Angiotensin-(1-7) in the Modulation of Angiotensin II-Dependent Cardiac Remodeling

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The Role of Angiotensin-(1-7) in the Modulation of Angiotensin II-Dependent Cardiac Remodeling
McCollum, LaTronya
Cardiac remodeling with associated changes in myocardial structure and function occurs in response to injury to the heart concomitant with chronic hypertension. The structural changes to the heart, including myocyte and vascular hypertrophy as well as interstitial and perivascular fibrosis, are attributed to a combination of both hemodynamic and humoral factors, such as angiotensin II (Ang II). Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide of the renin-angiotensin system with anti-proliferative properties which oppose the actions of Ang II. The purpose of this study was to determine whether Ang-(1-7) inhibits the Ang II-mediated growth of cardiac cells in vivo and in vitro and identify the molecular mechanisms for the inhibition of cardiac cell growth. 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 g/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 g/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. Our previous studies demonstrated that Ang-(1-7) reduces the growth of cardiac myocytes in vitro, in association with a reduction in ERK1/ERK2 mitogen-activated protein (MAP) kinase activities. Ang II infusion significantly increased phosphorylation of ERK1/ERK2 (0.89 ± 0.45, n = 6, p < 0.05) when compared to saline-infused animals (0.18 ± 0.07). In contrast, co-infusion with Ang-(1-7) significantly decreased the Ang II-induced ERK1/ERK2 activation. (0.19 ± 0.11). 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.
Angiotensin II
Cardiac Remodeling
Cardiac Fibrosis
Mitogen Activated Protein Kinase
Jordan, James E. (committee chair)
Tallant, E. Ann (committee member)
Diz, Debra I. (committee member)
Gallagher, Patricia E. (committee member)
Varagic, Jasmina (committee member)
2009-12-03T18:28:34Z (accessioned)
2010-06-18T18:59:29Z (accessioned)
2009-12-03T18:28:34Z (available)
2010-06-18T18:59:29Z (available)
2009-12-03T18:28:34Z (issued)
Physiology (discipline)
http://hdl.handle.net/10339/14858 (uri)
en_US (iso)
Wake Forest University
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)

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