[Abstract unavailable

Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110␣ isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exerciseinduced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110␣) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiacspecific transgenic mice with increased or decreased PI3K(p110␣) activity to the DCM model, and subjected PI3K(p110␣) transgenics to acute pressure overload (ascending aortic constriction). Lifespan, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110␣) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110␣) activity drastically shortened lifespan by Ϸ50%. Increased PI3K(p110␣) activity had a favorable effect on cardiac function and fibrosis in the pressureoverload model and attenuated pathological growth. PI3K(p110␣) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110␥) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110␣) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.heart failure ͉ signal transduction ͉ heart growth ͉ athlete's heart

Objective-Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110␣)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110␣) provides protection in a setting of MI is unknown, and PI3K(p110␣) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110␣) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110␣). Methods and Results-Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110␣) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110␣) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion-Activation of PI3K(p110␣) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110␣) represent new drug targets for heart failure.