Impaired cardiac SIRT1 activity by carbonyl stress contributes to aging-related ischemic intolerance

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...

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Published in:PloS one 2013-09, Vol.8 (9), p.e74050
Main Authors: Gu, Chunhu, Xing, Yuan, Jiang, Li, Chen, Mai, Xu, Ming, Yin, Yue, Li, Chen, Yang, Zheng, Yu, Lu, Ma, Heng
Format: Article
Language:English
Subjects:
Adaptation, Physiological
Age
Age Factors
Aging
Aging - metabolism
Aldehyde dehydrogenase
Aldehyde Dehydrogenase - metabolism
Aldehyde Dehydrogenase, Mitochondrial
Aldehydes
Aldehydes - adverse effects
Animals
Benzamides - administration & dosage
Benzodioxoles - administration & dosage
Biocompatibility
Carbonyl compounds
Carbonyls
Cardiomyocytes
Cell cycle
Data processing
Dehydrogenases
Disease Models, Animal
Enzyme Activation
Enzymes
Geriatrics
Heart
Heart diseases
Hospitals
House mouse
Hypoxia
Injuries
Intolerance
Ischemia
Laboratory animals
Male
Metabolism
Mice
Mice, Knockout
Muscle contraction
Myocardial Ischemia - metabolism
Myocardial Ischemia - physiopathology
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - physiopathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Older people
Oxidative stress
Physiology
Proteins
Reperfusion
Rodents
Senescence
SIRT1 protein
Sirtuin 1 - metabolism
Stress, Physiological - drug effects
Stresses
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cited_by cdi_FETCH-LOGICAL-c758t-117ce3ec4cd05def5faba0ac2fd0a735f21b5daeb7a9580c44daeeeec3b769343
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container_issue 9
container_start_page e74050
container_title PloS one
container_volume 8
creator Gu, Chunhu
Xing, Yuan
Jiang, Li
Chen, Mai
Xu, Ming
Yin, Yue
Li, Chen
Yang, Zheng
Yu, Lu
Ma, Heng
description 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
doi_str_mv 10.1371/journal.pone.0074050
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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&lt;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&lt;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&lt;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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0074050</identifier><identifier>PMID: 24040162</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptation, Physiological ; Age ; Age Factors ; Aging ; Aging - metabolism ; Aldehyde dehydrogenase ; Aldehyde Dehydrogenase - metabolism ; Aldehyde Dehydrogenase, Mitochondrial ; Aldehydes ; Aldehydes - adverse effects ; Animals ; Benzamides - administration &amp; dosage ; Benzodioxoles - administration &amp; dosage ; Biocompatibility ; Carbonyl compounds ; Carbonyls ; Cardiomyocytes ; Cell cycle ; Data processing ; Dehydrogenases ; Disease Models, Animal ; Enzyme Activation ; Enzymes ; Geriatrics ; Heart ; Heart diseases ; Hospitals ; House mouse ; Hypoxia ; Injuries ; Intolerance ; Ischemia ; Laboratory animals ; Male ; Metabolism ; Mice ; Mice, Knockout ; Muscle contraction ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - physiopathology ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - physiopathology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Older people ; Oxidative stress ; Physiology ; Proteins ; Reperfusion ; Rodents ; Senescence ; SIRT1 protein ; Sirtuin 1 - metabolism ; Stress, Physiological - drug effects ; Stresses</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e74050</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Gu et al. 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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&lt;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&lt;0.05). 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ALDH2 activation can restore this aging-related myocardial ischemic intolerance.</description><subject>Adaptation, Physiological</subject><subject>Age</subject><subject>Age Factors</subject><subject>Aging</subject><subject>Aging - metabolism</subject><subject>Aldehyde dehydrogenase</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehyde Dehydrogenase, Mitochondrial</subject><subject>Aldehydes</subject><subject>Aldehydes - adverse effects</subject><subject>Animals</subject><subject>Benzamides - administration &amp; dosage</subject><subject>Benzodioxoles - administration &amp; dosage</subject><subject>Biocompatibility</subject><subject>Carbonyl compounds</subject><subject>Carbonyls</subject><subject>Cardiomyocytes</subject><subject>Cell cycle</subject><subject>Data processing</subject><subject>Dehydrogenases</subject><subject>Disease Models, Animal</subject><subject>Enzyme Activation</subject><subject>Enzymes</subject><subject>Geriatrics</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Hospitals</subject><subject>House mouse</subject><subject>Hypoxia</subject><subject>Injuries</subject><subject>Intolerance</subject><subject>Ischemia</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Muscle contraction</subject><subject>Myocardial Ischemia - 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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&lt;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&lt;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&lt;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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24040162</pmid><doi>10.1371/journal.pone.0074050</doi><tpages>e74050</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2013-09, Vol.8 (9), p.e74050
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1431404814
source Publicly Available Content Database; PubMed Central
subjects Adaptation, Physiological
Age
Age Factors
Aging
Aging - metabolism
Aldehyde dehydrogenase
Aldehyde Dehydrogenase - metabolism
Aldehyde Dehydrogenase, Mitochondrial
Aldehydes
Aldehydes - adverse effects
Animals
Benzamides - administration & dosage
Benzodioxoles - administration & dosage
Biocompatibility
Carbonyl compounds
Carbonyls
Cardiomyocytes
Cell cycle
Data processing
Dehydrogenases
Disease Models, Animal
Enzyme Activation
Enzymes
Geriatrics
Heart
Heart diseases
Hospitals
House mouse
Hypoxia
Injuries
Intolerance
Ischemia
Laboratory animals
Male
Metabolism
Mice
Mice, Knockout
Muscle contraction
Myocardial Ischemia - metabolism
Myocardial Ischemia - physiopathology
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - physiopathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Older people
Oxidative stress
Physiology
Proteins
Reperfusion
Rodents
Senescence
SIRT1 protein
Sirtuin 1 - metabolism
Stress, Physiological - drug effects
Stresses
title Impaired cardiac SIRT1 activity by carbonyl stress contributes to aging-related ischemic intolerance
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