title: The protective effect of fasudil on the structure and function of cardiac mitochondria from rats with type 2 diabetes induced by streptozotocin with a high-fat diet is mediated by the attenuation of oxidative stress.
abstract: Dysfunction of cardiac mitochondria appears to play a substantial role in cardiomyopathy or myocardial dysfunction and is a promising therapeutic target for many cardiovascular diseases. We investigated the effect of the Rho/Rho-associated protein kinase (ROCK) inhibitor fasudil on cardiac mitochondria from rats in which diabetes was induced by a combination of streptozotocin (STZ) and a sustained high-fat diet. Eight weeks after diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ followed by a sustained high-fat diet, either fasudil (5 mg/kg bid) or equivalent volumes of saline (control) were administered over four weeks. Fasudil significantly protected against the histopathologic changes of cardiac mitochondria in diabetic rats. Fasudil significantly reduced the abundances of the Rho A, ROCK 1, and ROCK 2 proteins, restored the activities of succinate dehydrogenase (SDH) and monoamine oxidase (MAO) in cardiac mitochondria, inhibited the opening of the mitochondrial permeability transition pore, and decreased the total antioxidant capacity, as well as levels of malonyldialdehyde, hydroxy radical, reduced glutathione, and superoxide dismutase in heart. Fasudil improved the structures of cardiac mitochondria and increased both SDH and MAO activities in cardiac mitochondria. These beneficial effects may be associated with the attenuation of oxidative stress caused by fasudil treatment.
authors.affiliation: Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Zhong Road, Shanghai 200072, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Baoxin
authors.initials: B
authors.lastname: Liu
authors.forename: Shunping
authors.initials: S
authors.lastname: Zhou
authors.forename: Buchun
authors.initials: B
authors.lastname: Zhang
authors.forename: Yawei
authors.initials: Y
authors.lastname: Xu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D059305:Diet, High-Fat; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure*; D008995:Monoamine Oxidase / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013385:Succinate Dehydrogenase / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D013311:Streptozocin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D013385:Succinate Dehydrogenase; D008995:Monoamine Oxidase; D054460:rho-Associated Kinases; C049347:fasudil