title: Restoring Pharmacologic Preconditioning in the Aging Heart: Role of Mitophagy/Autophagy.
abstract: We previously reported that pretreatment with the potent antioxidant TEMPOL improves mitochondrial function and restores preconditioning in the aging heart. Because mitophagy is implicated in cardiac preconditioning and declines with age, this study was designed to investigate how age influences mitophagy in response to preconditioning and whether TEMPOL pretreatment improves it. Old (22-24 months) rats were pretreated with or without 4-week TEMPOL and compared with young (4-6 months) untreated rats. Cardioprotection induced by isoflurane (ISO) in vivo and in isolated cardiomyocytes in vitro was assessed following ischemia/reperfusion and simulated hypoxia/reoxygenation, respectively. Mitophagy was determined by comparing the levels/subcellular locations of key mitophagic markers using Western blotting and immunofluorescence techniques. ISO preconditioned the young but not old heart in vivo and in vitro. Aging impaired ISO-induced mitochondrial accumulation of PINK1 and Parkin, as well as mitochondrial ubiquitination, and baseline and ISO-induced autophagic flux assessed by LC3 puncta, membrane associated LC3-II and p62. Pretreatment with TEMPOL improved these processes and restored ISO preconditioning. Inhibition of autophagy abolished ISO-induced protection in cardiomyocytes from young and TEMPOL pretreated old rats. Thus, antioxidant pretreatment significantly improves mitophagic response to ISO in old myocardium, which may contribute to restoration of cardioprotection in senescent animals.
authors: Department of Anesthesiology, School of Medicine, Stony Brook University, New York.
authors: Li
authors: L
authors: Ma
authors: Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors: Jiang
authors: J
authors: Zhu
authors: Department of Anesthesiology, School of Medicine, Stony Brook University, New York.
authors: Qun
authors: Q
authors: Gao
authors: Department of Anesthesiology, School of Medicine, Stony Brook University, New York.
authors: Mario J
authors: MJ
authors: Rebecchi
authors: Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors: Qiang
authors: Q
authors: Wang
authors: Department of Anesthesiology, School of Medicine, Stony Brook University, New York.
authors: Lixin
authors: L
authors: Liu
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000502:physiology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001343:Autophagy / Q000502:physiology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D063306:Mitophagy / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011229:Preanesthetic Medication; D051381:Rats; D011916:Rats, Inbred F344; D013113:Spin Labels
chemical_list: D018685:Anesthetics, Inhalation; D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D007530:Isoflurane; C001803:tempol
keywords: Aging; Antioxidant; Cardiac preconditioning; Mitophagy/autophagy