Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function

Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardia c function, a transgenic mouse was generated. Cardiac tissue-specific overe xpression of the proapoptotic gene Caspase3 was induced by using the rat pr omoter of alpha -myosin heavy chain, a model that may represent a unique to ol for investigating new molecules and antiapoptotic therapeutic strategies . Cardiac-specific Caspase3 expression induced transient depression of card iac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgen ic mice showed increased infarct size and a pronounced susceptibility to di e. in this report, we document an unexpected property of the proapoptotic g ene caspase3 on cardiac contractility. Despite inducing ultrastructural dam age, Caspase3 does not trigger a full apoptotic response in the cardiomyocy te. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpres sion increases infarct size.