Endothelial and Cardiomyocyte PI3Kβ Divergently Regulate Cardiac Remodeling in Response to Ischemic Injury.

Aims Cardiac remodelling in the ischaemic heart determines prognosis in patients with ischaemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signalling pathways play a critical role in promoting angiogenesis and cell survival. However, the effect of PI3K beta in the ischaemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte (CM) PI3K beta in post-infarct cardiac remodelling. Methods and results PI3K beta catalytic subunit-p110 beta level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110 beta in endothelial cells (ECs) vs. CMs in response to myocardial ischaemic injury. Inactivation of endothelial p110 beta resulted in marked resistance to infarction and adverse cardiac remodelling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured ECs with p110 beta knockout or inhibition displayed preferential PI3K alpha/Akt/endothelial nitric oxide synthase signalling that consequently promoted protective signalling and angiogenesis. In contrast, mice with CM p110 beta-deficiency exhibited adverse post-infarct ventricular remodelling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of CMs to ischaemia-mediated cell death. Disruption of CM p110 beta signalling compromised nuclear p110 beta and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to CM death. A similar divergent response of PI3K beta endothelial and CM mutant mice was seen using a model of myocardial ischaemia-reperfusion injury. Conclusion These data demonstrate novel, differential, and cell-specific functions of PI3K beta in the ischaemic heart. While the loss of endothelial PI3K beta activity produces cardioprotective effects, CM PI3K beta is protective against myocardial ischaemic injury.