title: Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion.
abstract: OBJECTIVE
  Myocardial apoptosis is primarily triggered during reperfusion (R) through various mechanisms that may involve endonuclease to cleavage genomic DNA in the internucleosomal linker regions. However, the relative contribution of myocardial apoptosis to development of myocardial injury during R remains unknown. In the present study, we examined whether inhibition of apoptosis with aurintricarboxylic acid (ATA), an endonuclease inhibitor, during R reduces infarct size and improves regional contractile function.
  
  
  RESULTS
  In two groups of chronically-instrumented dogs, 1 h of left anterior descending (LAD) coronary occlusion was followed by 24 h of R with infusion of saline (control, n=8) or ATA (1 mg/kg/h, n=8) into the left atrium starting 5 min before R and continuing for 2 h. ATA significantly reduced apoptotic cells (TUNEL staining) in the peri-necrotic myocardium (12+/-1%* vs. 36+/-4%), consistent with the absence of DNA laddering. To confirm inhibition of apoptosis with ATA, densitometrically, Bcl-2 (% of normal myocardium) was significantly increased vs. control (102+/-12* vs. 68+/-9) and Bax as well as the activated caspase-3 were significantly reduced vs. control (108+/-17* vs. 194+/-42 and -29+/-4* vs. 174+/-43, respectively). ATA significantly improved segmental shortening (3.3+/-1.2* vs. -1.8+/-0.7%) and segmental work (79.3+/-11.3* vs. 7.1+/-5.8 mmHg/mm) in area at risk myocardium, and reduced infarct size (TTC staining, 27+/-0.2* vs. 37+/-0.5%), confirmed by lower plasma creatine kinase activity. In addition, myocardial blood flow (0.9+/-0.1* vs. 0.4+/-0.1 ml/min/g) and endothelial-dependent maximal vascular relaxation (119+/-6* vs. 49+/-8%) were significantly improved. Myeloperoxidase activity in area at risk myocardium, a marker for neutrophil accumulation, was also significantly reduced (17+/-4* vs. 138+/-28 Delta Abs/min).
  
  
  CONCLUSIONS
  These data suggest that the inhibition of apoptosis during R is associated with a reduction in infarction, improvement in regional contractile and vascular endothelial functions as well as augmentation in myocardial blood flow. *P<0.05 vs. control group.
authors.affiliation: Cardiothoracic Research Laboratory, The Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, GA 30308-2225, USA. zzhao@emory.edu
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Cullen D
authors.initials: CD
authors.lastname: Morris
authors.forename: Jason M
authors.initials: JM
authors.lastname: Budde
authors.forename: Ning-Ping
authors.initials: NP
authors.lastname: Wang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Muraki
authors.forename: He-Ying
authors.initials: HY
authors.lastname: Sun
authors.forename: Robert A
authors.initials: RA
authors.lastname: Guyton
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001312:Aurintricarboxylic Acid / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D003402:Creatine Kinase / Q000097:blood; D053938:DNA Fragmentation; D004285:Dogs; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D005260:Female; D020287:In Situ Nick-End Labeling; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000737:chemistry / Q000473:pathology*; D009195:Peroxidase / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011897:Random Allocation; D014665:Vasodilator Agents / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
chemical_list: D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014665:Vasodilator Agents; D051028:bcl-2-Associated X Protein; D001312:Aurintricarboxylic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D009195:Peroxidase; D003402:Creatine Kinase; D004720:Endonucleases; D053148:Caspase 3; D020169:Caspases