title: Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice.
abstract: Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria-specific O2(-) scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiquitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Cho
authors.forename: Aninda
authors.initials: A
authors.lastname: Basu
authors.forename: Anzhi
authors.initials: A
authors.lastname: Dai
authors.forename: Michael
authors.initials: M
authors.lastname: Heldak
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
mesh_terms: D000109:Acetylcholine; D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology*; D003470:Culture Media; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide; D019308:Palmitic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase
chemical_list: D003470:Culture Media; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D005947:Glucose; D000109:Acetylcholine
keywords: diabetic vascular complication; hyperglycemia; posttranslational modification; ubiquitin-proteasome system