| First Author | Guo D | Year | 2010 |
| Journal | Circ Res | Volume | 107 |
| Issue | 10 | Pages | 1275-89 |
| PubMed ID | 20847309 | Mgi Jnum | J:178189 |
| Mgi Id | MGI:5297659 | Doi | 10.1161/CIRCRESAHA.110.229054 |
| Citation | Guo D, et al. (2010) Loss of PI3Kgamma enhances cAMP-dependent MMP remodeling of the myocardial N-cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress. Circ Res 107(10):1275-89 |
| abstractText | 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 PI3Kgamma knockout (KO) mice to biomechanical stress. METHODS AND RESULTS: In response to pressure overload, PI3KgammaKO 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-3alpha. In contrast, isolated single cardiomyocytes from banded PI3KgammaKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KgammaKO 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 PI3Kgamma 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 PI3KgammaKO 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 PI3KgammaKO 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 PI3KgammaKO 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. |
