title: Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.
abstract: Histone deacetylases are recently identified to act as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of histone deacetylase (HDAC) in controlling cardiac performance in Type II diabetes and obesity remains unknown. Here, we determine whether HDAC inhibition attenuates high fat diet (HFD)-induced cardiac dysfunction and improves metabolic features. Adult mice were fed with either HFD or standard chow food for 24 weeks. Starting at 12 weeks, mice were divided into four groups randomly, in which sodium butyrate (1%), a potent HDAC inhibitor, was provided to chow and HFD-fed mice in drinking water, respectively. Glucose intolerance, metabolic parameters, cardiac function, and remodeling were assessed. Histological analysis and cellular signaling were examined at 24 weeks following euthanization of mice. HFD-fed mice demonstrated myocardial dysfunction and profound interstitial fibrosis, which were attenuated by HDAC inhibition. HFD-induced metabolic syndrome features insulin resistance, obesity, hyperinsulinemia, hyperglycemia, lipid accumulations, and cardiac hypertrophy, these effects were prevented by HDAC inhibition. Furthermore, HDAC inhibition attenuated myocyte apoptosis, reduced production of reactive oxygen species, and increased angiogenesis in the HFD-fed myocardium. Notably, HFD induced decreases in MKK3, p38, p38 regulated/activated protein kinase (PRAK), and Akt-1, but not p44/42 phosphorylation, which were prevented by HDAC inhibition. These results suggest that HDAC inhibition plays a critical role to preserve cardiac performance and mitigate metabolic disorders in obesity and diabetes, which is associated with MKK3/p38/PRAK pathway. The study holds promise in developing a new therapeutic strategy in the treatment of Type II diabetic-induced heart failure and metabolic disorders. J. Cell. Biochem. 118: 2395-2408, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.|Department of Emergency Medicine, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Du
authors.affiliation: Women and Infants Hospital, Brown University, Providence, Rhode Island.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
authors.forename: Yu Tina
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Patrycja M
authors.initials: PM
authors.lastname: Dubielecka
authors.affiliation: Department of Medicine, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institutes of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000818:Animals; D020148:Butyric Acid / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004452:Echocardiography; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000209:etiology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D020148:Butyric Acid; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse
keywords: CARDIAC FUNCTION; CARDIOVASCULAR DISEASE; DIABETES; HISTONE DEACETYLASE; METABOLIC SYNDROME; OBESITY