Cardiac functional improvement by a human Bcl-2 transgene in a mouse modelof ischemia/reperfusion injury

Background Apoptosis has been shown to contribute to myocardial reperfusion injury. It has been suggested that, in reducing the apoptotic component wi thin the ischemic area at risk, Bcl-2 overexpression could lead to a ventri cular function improvement. Methods Transgenic mice overexpressing the anti-apoptotic human Bcl-2 cDNA in heart were subjected to a 1-h left coronary artery occlusion followed by a 24-h reperfusion. At the end of the experiment, left ventricular functio n was assessed by two-dimensional echocardiography. After sacrifice, the ar ea at risk (AR) and the infarct area (IA) were determined by Evans blue and triphenyltetrazolium chloride staining, respectively The extent of apoptos is was assessed by the TUNEL, method. Non-transgenic littermates served as controls. Results Baseline AR was not different between Bcl-2 transgenic mice and the ir wild-type littermates. Ln contrast, left ventricular ejection fraction w as significantly improved in the transgenic mice line (61.25 +/- 4.0%) comp ared to non-transgenic littermates (43.2 +/- 5.0%, p<0.01). This functional amelioration was correlated with a significant reduction of infarct size i n transgenic animals (IA/AR 18.51 +/- 3.4% vs 50.83 +/- 8.4% in non-transge nic littermates). Finally, apoptotic nuclei were less numerous in transgeni c mice than in controls as quantified by TUNEL analysis (8.1 +/- 2.2% vs 20 .6 +/- 4.4%). Conclusions Bcl-2 overexpression is effective in reducing myocardial reperf usion injury and improving heart function. This benefit correlates with a r eduction of cardiomyocyte apoptosis. The apoptotic component of ischemia/re perfusion injury could therefore constitute a new therapeutic target in the acute phase of myocardial infarction. Copyright (C) 2000 John Wiley & Sons , Ltd.