Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure.
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| Abstract |
Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca(2+) transient. Oppositely, TG-DOCA myocytes presented enhanced Ca(2+) transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca(2+) handling, hypertrophy, and survival.
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| Authors | Pedro W Machado de Almeida, Marcos Barrouin Melo, Ricardo de Freitas Lima, Mariana Gavioli, Nivia M Santiago, Leonardo Greco, Itamar C G Jesus, Eduardo Nocchi, Amanda Parreira, Marcia N M Alves, Luciana Mitraud, Rodrigo Ribeiro Resende, Maria José Campagnole-Santos, Robson Augusto Souza Dos Santos, Silvia Guatimosim |
| Journal | Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 66 Issue 2 Pg. 389-95 (Aug 2015) ISSN: 1524-4563 [Electronic] United States |
| PMID | 26077567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2015 American Heart Association, Inc. |
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