Alamandine acts via MrgD to induce AMPK/NO activation against ANG II hypertrophy in cardiomyocytes

作者：Guedes de Jesus Itamar Couto; Scalzo Sergio; Alves Fabiana; Marques Kariny; Rocha Resende Cibele; Bader Michael; Santos Robson A Souza; Guatimosim Silvia^*

来源：American Journal of Physiology - Cell Physiology, 2018, 314(6): C702-C711.

DOI：10.1152/ajpcell.00153.2017

• AMP-activated protein kinase
• angiotensin system
• hypertrophy
• nitric oxide
• ventricular myocytes

The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. New members of this system have been characterized and shown to have biologically relevant actions. Alamandine and its receptor MrgD are recently identified components of RAS. In the cardiovascular system, alamandine actions included vasodilation, antihypertensive, and antifibrosis effects. Currently, the actions of alamandine on cardiomyocyles are unknown. Here our goal was twofold: 1) to unravel the signaling molecules activated by the alamandine/MrgD axis in cardiomyocytes; and 2) to evaluate the ability of this axis to prevent angiotensin II (ANG II)-induced hypertrophy. In cardiomyocytes from C57BL/6 mice, alamandine treatment induced an increase in nitric oxide (NO) production, which was blocked by D-Pro(7)-ANG-(1-7), a MrgD antagonist. This NO rise correlated with increased phosphorylation of AMPK. Alamandine-induced NO production was preserved in Mas(-/-) myocytes and lost in MrgD(-/-) cells. Binding of fluorescent-labeled alamandine was observed in wild-type cells, but it was dramatically reduced in MrgD(-/-) myocytes. We also assessed the consequences of prolonged alamandine exposure to cultured neonatal rat cardiomyocyles (NRCMs) treated with ANG II. Treatment of NRCMs with alamandine prevented ANG II-induced hypertrophy. Moreover, the antihypertrophic actions of alamandine were mediated via MrgD and NO. since they could be prevented by D-Pro(7)-ANG-(l-7) or inhibitors of NO synthase or AMPK. beta-Alanine, a MrgD agonist, recapitulated alamandine's cardioprotective effects in cardiomyocytes. Our data show that alamandine via MrgD induces AMPK/NO signaling to counterregulate ANG II-induced hypertrophy. These findings highlight the therapeutic potential of the alamandine/MrgD axis in the heart.

• 出版日期2018-6