title: Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.
abstract: BACKGROUND
  Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.
  
  
  METHODS
  Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments.
  
  
  RESULTS
  Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice.
  
  
  CONCLUSIONS
  HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. cyf988@126.com.
authors.forename: Youfang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. Jianfeng.Du@chartercare.org.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. tinazhao24@gmail.com.
authors.forename: Yu Tina
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Rhode Island Hospital, Brown University, Providence, RI, USA. lzhang1@lifespan.org.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Ultrasound, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China. lgr_feus@sina.com.
authors.forename: Guorong
authors.initials: G
authors.lastname: Lv
authors.affiliation: Department of Medicine, Rhode Island Hospital, Brown University, Providence, RI, USA. Szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, USA. g-qin@northwestern.edu.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. tzhao@bu.edu.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology*; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005355:Fibrosis; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D056572:Histone Deacetylase Inhibitors; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D020148:Butyric Acid; D003094:Collagen; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1