title: Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1.
abstract: Hyperglycemia-induced oxidative stress is implicated in the development of cardiomyopathy in diabetes that is associated with reduced adiponectin (APN) and heme oxygenase-1 (HO-1). Brahma-related gene 1 (Brg1) assists nuclear factor-erythroid-2-related factor-2 (Nrf2) to activate HO-1 to increase myocardial antioxidant capacity in response to oxidative stress. We hypothesized that reduced adiponectin (APN) impairs HO-1 induction which contributes to the development of diabetic cardiomyopathy, and that supplementation of APN may ameliorate diabetic cardiomyopathy by activating HO-1 through Nrf2 and Brg1 in diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were untreated or treated with APN adenovirus (1×10(9) pfu) 3 weeks after diabetes induction and examined and terminated 1 week afterward. Rat left ventricular functions were assessed by a pressure-volume conductance system, before the rat hearts were removed to perform histological and biochemical assays. Four weeks after diabetes induction, D rats developed cardiac hypertrophy evidenced as increased ratio of heart weight to body weight, elevated myocardial collagen I content, and larger cardiomyocyte cross-sectional area (all P<0.05 vs C). Diabetes elevated cardiac oxidative stress (increased 15-F2t-isoprostane, 4-hydroxynonenal generation, 8-hydroxy-2'-deoxyguanosine, and superoxide anion generation), increased myocardial apoptosis, and impaired cardiac function (all P<0.05 vs C). In D rats, myocardial HO-1 mRNA and protein expression were reduced which was associated with reduced Brg1 and nuclear Nrf2 protein expression. All these changes were either attenuated or prevented by APN. In primarily cultured cardiomyocytes (CMs) isolated from D rats or in the embryonic rat cardiomyocytes cell line H9C2 cells incubated with high glucose (HG, 25 mM), supplementation of recombined globular APN (gAd, 2μg/mL) reversed HG-induced reductions of HO-1, Brg1, and nuclear Nrf2 protein expression and attenuated cellular oxidative stress, myocyte size, and apoptotic cells. Inhibition of HO-1 by ZnPP (10μM) or small interfering RNA (siRNA) canceled all the above gAd beneficial effects. Moreover, inhibition of Nrf2 (either by the Nrf2 inhibitor luteolin or siRNA) or Brg1 (by siRNA) canceled gAd-induced HO-1 induction and cellular protection in CMs and in H9C2 cells incubated with HG. In summary, our present study demonstrated that APN reduced cardiac oxidative stress, ameliorated cardiomyocyte hypertrophy, and prevented left ventricular dysfunction in diabetes by concomitantly activating Nrf2 and Brg1 to facilitate HO-1 induction.
authors: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China.
authors: Haobo
authors: H
authors: Li
authors: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China; Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Weifeng
authors: W
authors: Yao
authors: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China.
authors: Michael G
authors: MG
authors: Irwin
authors: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China; Department of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Tingting
authors: T
authors: Wang
authors: Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Guangdong, China.
authors: Shuang
authors: S
authors: Wang
authors: Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Guangdong, China.
authors: Liangqing
authors: L
authors: Zhang
authors: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China; Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Guangdong, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China. Electronic address: zyxia@hku.hk.
authors: Zhengyuan
authors: Z
authors: Xia
mesh_terms: D052242:Adiponectin / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*; D016277:Ventricular Function, Left
chemical_list: D052242:Adiponectin; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D009687:Nuclear Proteins; D014157:Transcription Factors; D051547:Heme Oxygenase-1; C578929:Smarca4 protein, rat; D004265:DNA Helicases
keywords: Adiponectin; Brahma-related gene 1; Cardiac hypertrophy; Diabetes; Nuclear factor-erythroid-2-related factor-2