title: Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea.
abstract: OBJECTIVE
  Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol.
  
  
  METHODS
  Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg· kg(-1)· day(-1)) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis-inducing factor (AIF), caspase 3, Bcl-2, Bax, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting.
  
  
  RESULTS
  Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, α-SMA, and TGF-β1 as well as downregulation of Bcl-2 was markedly recovered by metoprolol, which was mediated by p38 MAPK.
  
  
  CONCLUSIONS
  Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, P. R. China.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Li
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Xue
authors.initials: X
authors.lastname: Ding
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: Dingyu
authors.initials: D
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Peng
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Dongyang
authors.initials: D
authors.lastname: Wang
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051033:Apoptosis Inducing Factor; D002317:Cardiovascular Agents; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D008790:Metoprolol; D009638:Norepinephrine