title: Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy.
abstract: OBJECTIVE
  The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy.
  
  
  METHODS
  The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured.
  
  
  RESULTS
  Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation.
  
  
  CONCLUSIONS
  Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ont., Canada N6A 4G5; Departments of Medicine and Pathology, The University of Western Ontario, London, Ont., Canada N6A 4G5.
authors.forename: Rui
authors.initials: R
authors.lastname: Ni
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ont., Canada N6A 4G5; Departments of Medicine and Pathology, The University of Western Ontario, London, Ont., Canada N6A 4G5.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.affiliation: Electrical and Computer Engineering, Medical Biophysics, Robarts Research Institute, University of Western Ontario, London, Ont., Canada N6A 4G5.
authors.forename: James C
authors.initials: JC
authors.lastname: Lacefield
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health; Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ont., Canada N6A 4G5.
authors.forename: Sydney
authors.initials: S
authors.lastname: Le Tissier
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ont., Canada N6A 4G5; Departments of Medicine and Pathology, The University of Western Ontario, London, Ont., Canada N6A 4G5. Electronic address: tpeng2@suda.edu.cn.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D058065:Diabetic Cardiomyopathies / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D013481:Superoxides; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Diabetic cardiomyopathy; ERK1/2; Mito-TEMPO; Mitochondria; Reactive oxygen species