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Updated: Sep 23, 2026
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during
Zhi-Qing Zhao1, Cullen D Morris, Jason M Budde
1Cardiothoracic 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
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.
Methods And 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.
Insights
Inhibiting myocardial apoptosis during reperfusion with aurintricarboxylic acid (ATA) significantly reduced infarct size and improved heart function. This study highlights apoptosis
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Ischemia-Reperfusion Injury
Background:
- Myocardial apoptosis, triggered by DNA cleavage during reperfusion, contributes to heart injury.
- The precise role of apoptosis in myocardial injury during reperfusion remains unclear.
Purpose of the Study:
- To investigate if inhibiting apoptosis with aurintricarboxylic acid (ATA), an endonuclease inhibitor, reduces infarct size and improves contractile function during reperfusion.
- To assess the impact of apoptosis inhibition on myocardial blood flow and vascular endothelial function.
Main Methods:
- Dogs underwent left anterior descending coronary artery occlusion followed by reperfusion.
- Aurintricarboxylic acid (ATA) or saline was infused during reperfusion.
- Apoptotic cells, DNA fragmentation, protein expression (Bcl-2, Bax, caspase-3), infarct size, myocardial blood flow, and neutrophil accumulation were assessed.
Main Results:
- ATA significantly reduced apoptotic cells and DNA laddering, confirming apoptosis inhibition.
- ATA treatment increased Bcl-2 expression and decreased Bax and activated caspase-3 levels.
- Significant improvements were observed in regional contractile function, infarct size reduction, myocardial blood flow, and endothelial-dependent vasodilation.
- Myeloperoxidase activity, a marker of neutrophil accumulation, was reduced by ATA.
Conclusions:
- Inhibition of myocardial apoptosis during reperfusion reduces infarction.
- Apoptosis inhibition improves regional contractile function and myocardial blood flow.
- Aurintricarboxylic acid (ATA) demonstrates protective effects against ischemia-reperfusion injury by modulating apoptosis.
