Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress
Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress
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DOI：
10.1161/circresaha.110.229054
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发表时间：
2010-11-12
影响因子：
20.1
通讯作者：
Oudit, Gavin Y.
中科院分区：
文献类型：
--
作者：
Guo, Danny;Kassiri, Zamaneh;Oudit, Gavin Y.
原理：机械传导和对生物力学应力的反应是心脏病的基本反应。磷脂酰肌醇3-激酶（PI 3 K）γ（与G蛋白偶联受体信号传导相关的同种型）的缺失导致心肌收缩力增加，但对压力超负荷的反应存在争议。目的：表征PI 3 K γ敲除（KO）小鼠对生物力学应力的分子和细胞反应。方法和结果：在对压力超负荷的反应中，尽管基础心肌收缩力增加，但与野生型小鼠相比，PI 3 K γ KO小鼠以加速的速率恶化。这些功能反应与Akt和GSK-3 α磷酸化受损相关。相比之下，从带状PI 3 K γ KO小鼠中分离的单个心肌细胞保持其过度收缩性，表明与细胞外基质的相互作用受损是带状PI 3 K γ KO小鼠中的主要缺陷。β-肾上腺素能刺激增加cAMP水平，CREB磷酸化增加，导致心肌细胞和心脏成纤维细胞中cAMP反应性基质金属蛋白酶（MMP）、MMP 2、MT 1-MMP和MMP 13表达增加。PI 3 K γ的缺失导致cAMP水平增加，MMP 2、MT 1-MMP和MMP 13的表达增加，以及MMP 2活化和胶原酶活性增加，以响应生物力学应力。在PI 3 K γ KO小鼠中，N-钙粘蛋白从粘附复合物中的选择性损失导致细胞粘附减少。β-受体阻滞剂普萘洛尔防止MMP的上调，而MMP抑制防止了两种疗法的不良重塑，防止了带状PI 3 K γ KO小鼠的功能恶化。在带状野生型小鼠，长期普萘洛尔防止不良重塑和收缩功能障碍与保存的N-钙粘蛋白levels.Conclusions：增强的倾向，发展心力衰竭的PI 3 K γ KO小鼠是由于cAMP依赖性上调MMP的表达和活性和解体的N-钙粘蛋白/β-连环蛋白细胞粘附复合物。β-受体阻滞剂治疗可防止这些变化，从而为这些药物提供了一种新的作用机制。(Circ Res. 2010;107：1275-1289）。
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.)