Loss of PI3Kγ enhances cAMP-dependent MMP remodeling of the myocardial N-cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress.
BACKGROUND
Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)γ, 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 PI3Kγ knockout (KO) mice to biomechanical stress.


RESULTS
In response to pressure overload, PI3KγKO 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-3α. In contrast, isolated single cardiomyocytes from banded PI3KγKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KγKO mice. β-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 PI3Kγ 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 PI3KγKO mice resulted in reduced cell adhesion. The β-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3KγKO 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 PI3KγKO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/β-catenin cell adhesion complex. β-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs.
Guo
Danny
D
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
Kassiri
Zamaneh
Z
Basu
Ratnadeep
R
Chow
Fung L
FL
Kandalam
Vijay
V
Damilano
Federico
F
Liang
Wenbin
W
Izumo
Seigo
S
Hirsch
Emilio
E
Penninger
Josef M
JM
Backx
Peter H
PH
Oudit
Gavin Y
GY
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism*; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology; D010766:Phosphorylation; D011433:Propranolol / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D015703:Antigens, CD; C050361:CDH2 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C507096:Mmp14 protein, mouse; D051176:beta Catenin; D011433:Propranolol; D000242:Cyclic AMP; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D053511:Matrix Metalloproteinase 14