Beta-3 Adrenoreceptors protect from hypertrophic remodelling through AMP-Activated Protein Kinase and Autophagy.
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Emilie Dubois-Deruy, Roselle Gelinas, Christophe Beauloye, Hrag Esfahani, Chantal Dessy, Luc Bertrand, Jean-Luc Balligand
2020
Abstract
Aims: The abundance of beta3-adrenergic receptors (β3-ARs) is upregulated in diseased human myocardium. We previously showed that cardiac-specific expression of β3-AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analyzed signalling pathways involved in the anti-hypertrophic effect of β3-AR. Methods: In vitro hypertrophic responses to phenylephrine (PE) were analyzed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human β3-AR (AdVhβ3). We confirmed results in mice with cardiomyocyte-specific moderate expression of human β3-AR (β3-TG) and WT littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. Results: We observed a colocalization of β3-AR with the AMP-activated protein kinase (AMPK) both in neonatal rat andin adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172-AMPK (/2, p=0.0487) and phosphorylation of Ser79- acetyl-CoA carboxylase (ACC) (/2.6, p=0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (x2.5, p=0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice, but restored to basal levels in β3-AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti-hypertrophic effect of β3-AR in response to PE in NRVM (x1.3, p<0.0001). Concomitant with hypertrophy, autophagy measured by microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio and p62 abundance was decreased by PE in NRVM (/2.6, p=0.0010 and x3, p=0.0016, respectively) or TAC in WT mice (/5.4, p=0.0159); and preserved in human β3-AR expressing cells and mice, together with reduced hypertrophy.
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Date 2020-01-14
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