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

Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.

Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline ('norepinephrine')] release, stimulation of alpha(1)-ARs (alpha(1)-adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5)P(3) generation and the development of arrhythmias. In the present study, we examined the effect of increased alpha(1A)-AR drive on these responses. In hearts from non-transgenic mice (alpha(1A)-WT), Ins(1,4,5)P(3) generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5)P(3) response was observed in hearts from transgenic mice with 66-fold overexpression of alpha(1A)-AR (alpha(1A)-TG). This was despite the fact that alpha(1A)-TG hearts had 8-10-fold higher PLC responses to NE than alpha(1A)-WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5)P(3), PtdIns(4,5)P(2), responded to ischaemia and reperfusion similarly in alpha(1A)-WT and alpha(1A)-TG mice. Thus the lack of Ins(1,4,5)P(3) generation in alpha(1A)-TG mice is not caused by limited availability of PtdIns(4,5)P(2). Overall, alpha(1)-AR-mediated PLC activity was markedly enhanced in alpha(1A)-WT mice under reperfusion conditions, but responses in alpha(1A)-TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5)P(3) generation after 30 min of ischaemic insult in alpha(1A)-WT mice. However, the precursor lipid PtdIns(4,5)P(2) was also reduced by preconditioning, whereas heightened alpha(1A)-AR activity did not influence PtdIns(4,5)P(2) responses in reperfusion. Thus preconditioning and alpha(1A)-AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5)P(3) generation. These studies demonstrate a selective inhibitory action of heightened alpha(1A)-AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion.