Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress

Rationale: Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)gamma, the isoform linked to G protein-coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial. Objective: To characterize molecular and cellular responses of the PI3K gamma knockout (KO) mice to biomechanical stress. Methods and Results: In response to pressure overload, PI3K gamma KO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3 alpha. In contrast, isolated single cardiomyocytes from banded PI3K gamma KO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3K gamma KO mice. beta-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K gamma resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3K gamma KO mice resulted in reduced cell adhesion. The beta-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3K gamma KO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels. Conclusions: The enhanced propensity to develop heart failure in the PI3K gamma KO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/beta-catenin cell adhesion complex. beta-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs. (Circ Res. 2010;107:1275-1289.)