title: PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes.
abstract: Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.
authors: Department of Anesthesiology, The University of Hong Kong, China.
authors: Yanan
authors: Y
authors: Liu
authors: Shaoqing
authors: S
authors: Lei
authors: Xia
authors: X
authors: Gao
authors: Xiaowen
authors: X
authors: Mao
authors: Tingting
authors: T
authors: Wang
authors: Gordon T
authors: GT
authors: Wong
authors: Paul M
authors: PM
authors: Vanhoutte
authors: Michael G
authors: MG
authors: Irwin
authors: Zhengyuan
authors: Z
authors: Xia
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000517:prevention & control*; D015237:Dinoprost / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D028421:Isoprostanes / Q000097:blood; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D016166:Free Radical Scavengers; D007211:Indoles; D028421:Isoprostanes; D008301:Maleimides; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; C099154:ruboxistaurin; D015237:Dinoprost; D019255:NADPH Oxidases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000111:Acetylcysteine