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Application of Zinc-bis-(DL-Hydrogensaspartate) Does Not Reduce Apoptotic Cell Death in Myocardial Infarction in the Rat Heart

Medizinische Klinik I, RTWH University Hospital Aachen, Germany, Ernst.Schwarz{at}cshs.org, Division of Cardiology, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, Los Angeles, California

Tanja Tussing, MD

Medizinische Klinik I, RTWH University Hospital Aachen, Germany

Erik Skobel, MD

Medizinische Klinik I, RTWH University Hospital Aachen, Germany

Bernd Klosterhalfen, MD

Medizinische Klinik I, RTWH University Hospital Aachen, Germany

Damian Domanski, MD, PhD

Division of Cardiology, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, Los Angeles, California

Justin E. Fuess, MD

Division of Cardiology, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, Los Angeles, California

Background: Early studies in different stress models have shown potential beneficial effects of exogenous zinc application with reduction in the rate of apoptotic cell death. This has not been shown in models of myocardial infarction. Methods: Rats were exposed to either brief episodes of acute ischemia followed by reperfusion (phase 1) or chronic coronary occlusion (phase 2). Animals were either treated with zinc or vehicle. Groups 1 and 3 received zinc-bis-(DL-hydrogenaspartate) 10 mg/kg body weight as a single 5-mL bolus administered intraperitoneally 24 hours prior to coronary occlusion, groups 2 and 4 received saline. The infarct sizes were determined by triphenyltetrazolium chloride staining and expressed at relative areas to areas of ischemia. Histological slices of the rat’s myocardium at the border zones of the infarcts were stained with the TUNEL method to assess for apoptosis. Animals in groups 5, 7, and 9 received zinc, given once before and then repeated every 4 days after coronary occlusion, whereas groups 6, 8, and 10 received saline. Animals were observed for observation periods of 13 (groups 9 and 10), 16 (groups 7 and 8), or 19 weeks (groups 5 and 6), respectively. Two-dimensional echocardiography was performed to measure ejection fraction (EF) at baseline and at the end of the observation periods. TUNEL staining was used to detect and quantify apoptosis rate in the border zones of infarcts after the hearts were excised. Results: Infarct sizes were 49% + 22% in group 1 (zinc + 30 minutes ischemia + 30 minutes reperfusion); 48% + 10% in group 2 (vehicle + 30 minutes ischemia + 30 minutes reperfusion); 42% + 11% in group 3 (zinc + 60 minutes ischemia + 30 minutes reperfusion); and 41% + 23% in group 4 (vehicle + 60 minutes ischemia + 60 minutes reperfusion). In group 1, 11% + 6% of cells were apoptotic compared to 12% + 4% in group 2, 16% + 9% in group 3, and 17% + 7% in group 4 (P > .05). In phase 2, echocardiography revealed a significant reduction in EF in all groups after coronary occlusion. There were no significant differences in EF between the 5 groups at baseline and at follow-up. TUNEL staining did not reveal any significant apoptosis after 13 to 19 weeks. Conclusion: Application of zinc failed to result in reduction of infarct size after temporary coronary occlusion followed by reperfusion and did not demonstrate any reduction in apoptotic cell death. In chronic coronary occlusion, zinc also did not improve EF compared to controls in the presented model in rats. The mechanisms involved in antiapoptotic effects seem to be more complex and might not be inducible by simple zinc injections.

Key Words: ischemia • reperfusion • zinc • apoptosis • infarct size • myocardial protection • rats

This version was published on September 1, 2009

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 3, 215-221 (2009)
DOI: 10.1177/1074248409340159


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