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

L eft ventricular hypertrophy is the most common cardiac complication of hypertension. Although the initial adaptations associated with cardiac hypertrophy are compensatory, ultimately abnormal ventricular function including diastolic dysfunction (impaired relaxation) and often heart failure may develop. 1 Activation of the renin–angiotensin system and its main effector peptide angiotensin II (Ang II), acting on the Ang II type 1 receptor, has been considered an important part of the cascade leading to left ventricular hypertrophy and cardiac fibrosis. Recent work, however, examining the effects of Ang II infusion using cardiomyocyte and vascular smooth muscle–specific Ang II type 1 receptor knockouts suggests that the hypertension-induced increase in afterload, rather than direct Ang II–Ang II type 1 receptor signaling in the heart, is the key factor that promotes hypertrophic responses. 2 The renin–angiotensin system peptide Ang-(1–7), which is generated from Ang II by the action of carboxypeptidases, such as ACE2, 3 exhibits actions that are mainly opposite to those of Ang II, including vasodilatory and antifibrotic effects. 4 In this issue, Machado de Almeida et al 5 report a series of interesting observations that suggest that in an Ang-(1–7) transgenic line, TGR(A1–7)3292, there is cardioprotection from deoxycorticosterone acetate (DOCA)–salt induced hypertension which is independent of blood pressure. The latter conclusion is not unexpected considering the strong evidence against an antihypertensive effect of Ang-(1–7): (1) acute infusions of supraphysiologic concentrations of this peptide do not lower blood pressure in mice, 3 (2) a 4-week continuous infusion of Ang-(1–7) did not decrease blood pressure in DOCA-treated Sprague-Dawley (SD) rats, 6 (3) acutely Ang-(1–7) does not attenuate the hypertensive effect of infused Ang II, and a blocker of the Mas receptor also does not worsen the blood pressure response to infused Ang II, 3 and (4) the antihypertensive effects of an Ang II antagonist are not altered by the concomitant administration of the Ang-(1–7) receptor blocker. 7 Notwithstanding these observations, the rat transgenic TGR(A1–7)3292 used displayed an attenuated hypertensive response to DOCA, and appropriate experiments were performed to show that the observed cardioprotective effects were not found in control animals with hydralazine-induced attenuated blood pressure levels. 5 Previous studies have shown cardioprotective effects of Ang-(1–7). The question then arises: how does Ang-(1–7) act directly on car-diomyocytes to reduce hypertrophic responses? Machado de Almeida et al 5 examines this question in detail using the DOCA hypertension model in SD control and TGR(A1–7)3292 rats by investigating cardiomyocyte-specific molecular …