title: In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.
abstract: BACKGROUND
  Diabetes is associated with increased risk of mortality as a consequence of acute myocardial infarction. This study determined whether rosiglitazone (ROSI) could reduce myocardial infarction after ischemia/reperfusion injury.
  
  
  RESULTS
  Male Lewis rats were anesthetized, and the left anterior descending coronary artery was ligated for 30 minutes. After reperfusion for 24 hours, the ischemic and infarct sizes were determined. ROSI at 1 and 3 mg/kg IV reduced infarct size by 30% and 37%, respectively (P<0.01 versus vehicle). Pretreatment with ROSI (3 mg. kg(-1). d(-1) PO) for 7 days also reduced infarct size by 24% (P<0.01). ROSI also improved ischemia/reperfusion-induced myocardial contractile dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in ROSI-treated rats. ROSI reduced the accumulation of neutrophils and macrophages in the ischemic heart by 40% and 43%, respectively (P<0.01). Ischemia/reperfusion induced upregulation of CD11b/CD18 and downregulation of L-selectin on neutrophils and monocytes; these effects were significantly attenuated in ROSI-treated animals. Likewise, intercellular adhesion molecule-1 expression in ischemic hearts was markedly diminished by ROSI, as was the ischemia/reperfusion-stimulated upregulation of monocyte chemoattractant protein-1.
  
  
  CONCLUSIONS
  ROSI reduced myocardial infarction and improved contractile dysfunction caused by ischemia/reperfusion injury. The cardioprotective effect of ROSI was most likely due to inhibition of the inflammatory response.
authors.affiliation: Department of Cardiovascular Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Yue Tl
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Bao
authors.forename: P K
authors.initials: PK
authors.lastname: Narayanan
authors.forename: A
authors.initials: A
authors.lastname: Bril
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.forename: P G
authors.initials: PG
authors.lastname: Lysko
authors.forename: J L
authors.initials: JL
authors.lastname: Gu
authors.forename: R
authors.initials: R
authors.lastname: Boyce
authors.forename: D M
authors.initials: DM
authors.lastname: Zimmerman
authors.forename: T K
authors.initials: TK
authors.lastname: Hart
authors.forename: R E
authors.initials: RE
authors.lastname: Buckingham
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D048909:Diabetes Complications; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*
chemical_list: D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone