Uncoupling between enhanced excitation–contraction coupling and the response to heart disease: Lessons from the PI3Kγ knockout murine model

The heart is a mechanosensitive organ that adapts its morphology to changing hemodynamic conditions via a process named mechanotransduction, which is the primary means of detecting mechanical stress in the extracellular environment. In the heart, mechanical signals are propagated into the intracellular space primarily via cell adhesion complexes and are subsequently transmitted from cell to cell via paracrine signaling. Enhanced excitation–contraction coupling increases myocardial contractility in various experimental models. However, these animal models routinely show increased susceptibility to biomechanical stress with the development of early ventricular dilation and reduced systolic function in the setting of adverse myocardial remodeling. The enhanced susceptibility of the PI3Kγ knockout mice to biomechanical stress is linked to a cAMP-dependent up-regulation of matrix metalloproteinase with a loss of N-cadherin mediated cell adhesion. Enhancing cell–cell adhesion and cell–ECM interaction will promote the salutary effects of enhanced intracellular Ca2+ cycling on whole heart function and booster the therapeutic potential of normalizing intracellular Ca2+ cycling in patients with heart failure.

Research Highlights
► Loss of PI3Kγ enhances cAMP levels and enhances basal myocardial contractility.
► Loss of PI3Kγ enhances susceptibility to biomechanical stress and early-onset heart failure.
► Activation of MMP and loss of N-cadherin mediated cell adhesion are mediators of this adverse remodeling.
► These findings provide insight into other animal models with elevated Ca2+ cycling but an inability to rescue heart failure.
► Chronic β-blocker therapy exerts a novel mechanism in preventing adverse myocardial remodeling.