title: Impaired cardiac SIRT1 activity by carbonyl stress contributes to aging-related ischemic intolerance.
abstract: Reactive aldehydes can initiate protein oxidative damage which may contribute to heart senescence. Sirtuin 1 (SIRT1) is considered to be a potential interventional target for I/R injury management in the elderly. We hypothesized that aldehyde mediated carbonyl stress increases susceptibility of aged hearts to ischemia/reperfusion (I/R) injury, and elucidate the underlying mechanisms with a focus on SIRT1. Male C57BL/6 young (4-6 mo) and aged (22-24 mo) mice were subjected to myocardial I/R. Cardiac aldehyde dehydrogenase (ALDH2), SIRT1 activity and protein carbonyls were assessed. Our data revealed that aged heart exhibited increased endogenous aldehyde/carbonyl stress due to impaired ALDH2 activity concomitant with blunted SIRT1 activity (P<0.05). Exogenous toxic aldehydes (4-HNE) exposure in isolated cardiomyocyte verified that aldehyde-induced carbonyl modification on SIRT1 impaired SIRT1 activity leading to worse hypoxia/reoxygenation (H/R) injury, which could all be rescued by Alda-1 (ALDH2 activator) (all P<0.05). However, SIRT1 inhibitor blocked the protective effect of Alda-1 on H/R cardiomyocyte. Interestingly, myocardial I/R leads to higher carbonylation but lower activity of SIRT1 in aged hearts than that seen in young hearts (P<0.05). The application of Alda-1 significantly reduced the carbonylation on SIRT1 and markedly improved the tolerance to in vivo I/R injury in aged hearts, but failed to protect Sirt1(+/-) knockout mice against myocardial I/R injury. This was verified by Alda-1 treatment improved postischemic contractile function recovery in ex vivo perfused aged but not in Sirt1(+/-) hearts. Thus, aldehyde/carbonyl stress is accelerated in aging heart. These results provide a new insight that impaired cardiac SIRT1 activity by carbonyl stress plays a critical role in the increased susceptibility of aged heart to I/R injury. ALDH2 activation can restore this aging-related myocardial ischemic intolerance.
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chunhu
authors.initials: C
authors.lastname: Gu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xing
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Mai
authors.initials: M
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Yue
authors.initials: Y
authors.lastname: Yin
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Heng
authors.initials: H
authors.lastname: Ma
mesh_terms: D000222:Adaptation, Physiological; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000009:adverse effects; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D052117:Benzodioxoles / Q000008:administration & dosage; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000860:Hypoxia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D056564:Sirtuin 1
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