RRC ID 31870
Author Nakaoka M, Iwai-Kanai E, Katamura M, Okawa Y, Mita Y, Matoba S.
Title An alpha-adrenergic agonist protects hearts by inducing Akt1-mediated autophagy.
Journal Biochem Biophys Res Commun
Abstract Alpha-adrenergic agonists is known to be protective in cardiac myocytes from apoptosis induced by beta-adrenergic stimulation. Although there has been a recent focus on the role of cardiac autophagy in heart failure, its role in heart failure with adrenergic overload has not yet been elucidated. In the present study, we investigated the contribution of autophagy to cardiac failure during adrenergic overload both in vitro and in vivo. Neonatal rat cardiac myocytes overexpressing GFP-tagged LC3 were prepared and stimulated with the alpha1-adrenergic agonist, phenylephrine (PE), the beta-adrenergic agonist, isoproterenol (ISO), or norepinephrine (NE) in order to track changes in the formation of autophagosomes in vitro. All adrenergic stimulators increased cardiac autophagy by stimulating autophagic flux. Blocking autophagy by the knockdown of autophagy-related 5 (ATG5) exacerbated ISO-induced apoptosis and negated the anti-apoptotic effects of PE, which indicated the cardioprotective role of autophagy during adrenergic overload. PE-induced cardiac autophagy was mediated by the PI3-kinase/Akt pathway, but not by MEK/ERK, whereas both pathways mediated the anti-apoptotic effects of PE. Knock down of Akt1 was the most essential among the three Akt family members examined for the induction of cardiac autophagy. The four-week administration of PE kept the high level of cardiac autophagy without heart failure in vivo, whereas autophagy levels in a myocardium impaired by four-week persistent administration of ISO or NE were the same with the control state. These present study indicated that cardiac autophagy played a protective role during adrenergic overload and also that the Akt pathway could mediate cardiac autophagy for the anti-apoptotic effects of the alpha-adrenergic pathway.
Volume 456(1)
Pages 250-6
Published 2015-1-2
DOI 10.1016/j.bbrc.2014.11.067
PII S0006-291X(14)02097-X
PMID 25446079
MeSH Adrenergic alpha-Agonists / pharmacology* Animals Animals, Newborn Apoptosis Autophagy* Cardiotonic Agents / pharmacology Green Fluorescent Proteins / metabolism Heart / drug effects* Heart Failure / metabolism* Heart Failure / prevention & control Isoproterenol / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Norepinephrine / pharmacology Phenylephrine / pharmacology Proto-Oncogene Proteins c-akt / metabolism* Rats TOR Serine-Threonine Kinases / metabolism
IF 2.985
Times Cited 13
Mice RBRC00806