title: Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice.
abstract: Diabetes causes energy metabolism disturbance and may lead to cardiac dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects cardiac function from myocardial damage. Therefore, understanding of its roles in diabetic heart is critical for developing new therapeutics targeting ALDH2 and mitochondrial function for diabetic hearts. This study investigated the impact of ALDH2 deficiency on diastolic function and energy metabolism in diabetic mice. Diabetes was induced in ALDH2 knockout and wild-type mice by streptozotocin. Cardiac function was determined by echocardiography. Glucose uptake, energy status, and metabolic profiles were used to evaluate cardiac energy metabolism. The association between ALDH2 polymorphism and diabetes was also analyzed in patients. Echocardiography revealed preserved systolic function and impaired diastolic function in diabetic ALDH2-deficient mice. Energy reserves (phosphocreatine/adenosine triphosphate ratio) were reduced in the diabetic mutants and were associated with diastolic dysfunction. Western blot analysis showed that diabetes induces accumulated lipid peroxidation products and escalated AMP-activated protein kinase-LKB1 pathway. Further, ALDH2 deficiency exacerbated the diabetes-induced deficient myocardial glucose uptake and other perturbations of metabolic profiles. Finally, ALDH2 mutations were associated with worse diastolic dysfunction in diabetic patients. Together, our results demonstrate that ALDH2 deficiency and resulting energy metabolism disturbance is a part of pathology of diastolic dysfunction of diabetic hearts, and suggest that patients with ALDH2 mutations are vulnerable to diabetic damage.
  
  
  
  ALDH2 deficiency exacerbates diastolic dysfunction in early diabetic hearts. ALDH2 deficiency triggers decompensation of metabolic reserves and energy metabolism disturbances in early diabetic hearts. ALDH2 deficiency potentiates oxidative stress and AMPK phosphorylation induced by diabetes via post-translational regulation of LKB1. Diabetic patients with ALDH2 mutations are predisposed to worse diastolic dysfunction.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Shen
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Institute of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Han
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Chaoneng
authors.initials: C
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.|Institute of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China. jbge@zs-hospital.sh.cn.|Institute of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China. jbge@zs-hospital.sh.cn.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai, 200032, People's Republic of China. sun.aijun@zs-hospital.sh.cn.|Institute of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China. sun.aijun@zs-hospital.sh.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D003971:Diastole; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000447:Aldehydes; C096127:ALDH2 protein, human; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C027576:4-hydroxy-2-nonenal
keywords: ALDH2; Diabetes; Diastolic function; Energy metabolism