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Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function.
Free Radic Biol Med. 2014 Jun; 71:208-20.FR

Abstract

Cardiac aging is associated with compromised myocardial function and morphology although the underlying mechanism remains elusive. Aldehyde dehydrogenase 2 (ALDH2), an essential mitochondrial enzyme governing cardiac function, displays polymorphism in humans. This study was designed to examine the role of ALDH2 in aging-induced myocardial anomalies. Myocardial mechanical and intracellular Ca(2+) properties were examined in young (4-5 months) and old (26-28 months) wild-type and ALDH2 transgenic mice. Cardiac histology, mitochondrial integrity, O2(-) generation, apoptosis, and signaling cascades, including AMPK activation and Sirt1 level were evaluated. Myocardial function and intracellular Ca(2+) handling were compromised with advanced aging; the effects were accentuated by ALDH2. Hematoxylin and eosin and Masson trichrome staining revealed cardiac hypertrophy and interstitial fibrosis associated with greater left-ventricular mass and wall thickness in aged mice. ALDH2 accentuated aging-induced cardiac hypertrophy but not fibrosis. Aging promoted O2(-) release, apoptosis, and mitochondrial injury (mitochondrial membrane potential, levels of UCP-2 and PGC-1α), and the effects were also exacerbated by ALDH2. Aging dampened AMPK phosphorylation and Sirt1, the effects of which were exaggerated by ALDH2. Treatment with the ALDH2 activator Alda-1 accentuated aging-induced O2(-) generation and mechanical dysfunction in cardiomyocytes, the effects of which were mitigated by cotreatment with activators of AMPK and Sirt1, AICAR, resveratrol, and SRT1720. Examination of human longevity revealed a positive correlation between life span and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may accentuate myocardial remodeling and contractile dysfunction in aging, possibly through AMPK/Sirt1-mediated mitochondrial injury.

Authors+Show Affiliations

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China 710032; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China. Electronic address: jbge@zs-hospital.sh.cn.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China 710032; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address: jren@uwyo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24675227

Citation

Zhang, Yingmei, et al. "Mitochondrial Aldehyde Dehydrogenase 2 Accentuates Aging-induced Cardiac Remodeling and Contractile Dysfunction: Role of AMPK, Sirt1, and Mitochondrial Function." Free Radical Biology & Medicine, vol. 71, 2014, pp. 208-20.
Zhang Y, Mi SL, Hu N, et al. Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radic Biol Med. 2014;71:208-20.
Zhang, Y., Mi, S. L., Hu, N., Doser, T. A., Sun, A., Ge, J., & Ren, J. (2014). Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radical Biology & Medicine, 71, 208-20. https://doi.org/10.1016/j.freeradbiomed.2014.03.018
Zhang Y, et al. Mitochondrial Aldehyde Dehydrogenase 2 Accentuates Aging-induced Cardiac Remodeling and Contractile Dysfunction: Role of AMPK, Sirt1, and Mitochondrial Function. Free Radic Biol Med. 2014;71:208-20. PubMed PMID: 24675227.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. AU - Zhang,Yingmei, AU - Mi,Shou-Ling, AU - Hu,Nan, AU - Doser,Thomas A, AU - Sun,Aijun, AU - Ge,Junbo, AU - Ren,Jun, Y1 - 2014/03/24/ PY - 2013/12/22/received PY - 2014/03/14/revised PY - 2014/03/17/accepted PY - 2014/3/29/entrez PY - 2014/3/29/pubmed PY - 2015/1/7/medline KW - ALDH2 KW - AMPK KW - Aging KW - Cardiac geometry KW - Contractile function KW - Free radicals KW - Sirt1 SP - 208 EP - 20 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 71 N2 - Cardiac aging is associated with compromised myocardial function and morphology although the underlying mechanism remains elusive. Aldehyde dehydrogenase 2 (ALDH2), an essential mitochondrial enzyme governing cardiac function, displays polymorphism in humans. This study was designed to examine the role of ALDH2 in aging-induced myocardial anomalies. Myocardial mechanical and intracellular Ca(2+) properties were examined in young (4-5 months) and old (26-28 months) wild-type and ALDH2 transgenic mice. Cardiac histology, mitochondrial integrity, O2(-) generation, apoptosis, and signaling cascades, including AMPK activation and Sirt1 level were evaluated. Myocardial function and intracellular Ca(2+) handling were compromised with advanced aging; the effects were accentuated by ALDH2. Hematoxylin and eosin and Masson trichrome staining revealed cardiac hypertrophy and interstitial fibrosis associated with greater left-ventricular mass and wall thickness in aged mice. ALDH2 accentuated aging-induced cardiac hypertrophy but not fibrosis. Aging promoted O2(-) release, apoptosis, and mitochondrial injury (mitochondrial membrane potential, levels of UCP-2 and PGC-1α), and the effects were also exacerbated by ALDH2. Aging dampened AMPK phosphorylation and Sirt1, the effects of which were exaggerated by ALDH2. Treatment with the ALDH2 activator Alda-1 accentuated aging-induced O2(-) generation and mechanical dysfunction in cardiomyocytes, the effects of which were mitigated by cotreatment with activators of AMPK and Sirt1, AICAR, resveratrol, and SRT1720. Examination of human longevity revealed a positive correlation between life span and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may accentuate myocardial remodeling and contractile dysfunction in aging, possibly through AMPK/Sirt1-mediated mitochondrial injury. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/24675227/Mitochondrial_aldehyde_dehydrogenase_2_accentuates_aging_induced_cardiac_remodeling_and_contractile_dysfunction:_role_of_AMPK_Sirt1_and_mitochondrial_function_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(14)00135-X DB - PRIME DP - Unbound Medicine ER -