title: An alpha-adrenergic agonist protects hearts by inducing Akt1-mediated autophagy.
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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Nakaoka
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan; Faculty of Health Care, Tenri Health Care University, 80-1 Bessho-cho, Tenri, Nara 632-0018, Japan. Electronic address: eriik@tenriyorozu-u.ac.jp.
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Katamura
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Okawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mita
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001343:Autophagy; D002316:Cardiotonic Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000378:metabolism* / Q000517:prevention & control; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D002316:Cardiotonic Agents; D049452:Green Fluorescent Proteins; D010656:Phenylephrine; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D007545:Isoproterenol; D009638:Norepinephrine
keywords: Adrenergic overload; Apoptosis; Autophagy; Cardioprotection