Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure.

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.

de Almeida PW ，Melo MB ，Lima Rde F ，Gavioli M ，Santiago NM ，Greco L ，Jesus IC ，Nocchi E ，Parreira A ，Alves MN ，Mitraud L ，Resende RR ，Campagnole-Santos MJ ，Dos Santos RA ，Guatimosim S ... -  《-》

Lifetime overproduction of circulating Angiotensin-(1-7) attenuates deoxycorticosterone acetate-salt hypertension-induced cardiac dysfunction and remodeling.

Santiago NM ，Guimarães PS ，Sirvente RA ，Oliveira LA ，Irigoyen MC ，Santos RA ，Campagnole-Santos MJ ... -  《-》

Angiotensins and the heart: is angiotensin-(1-7) cardioprotective?

Wysocki J ，Wilsbacher L ，Batlle D 《-》

Cardiac type-1 angiotensin II receptor status in deoxycorticosterone acetate-salt hypertension in rats.

Fareh J ，Touyz RM ，Schiffrin EL ，Thibault G ... -  《HYPERTENSION》

Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension.

Klanke B ，Cordasic N ，Hartner A ，Schmieder RE ，Veelken R ，Hilgers KF ... -  《-》