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Competitive displacement of phosphoinositide 3-kinase from -adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling

Department of Medicine, Cell Biology, and Molecular Genetics, Duke University Medical Center, Durham, North Carolina

Submitted 13 November 2005 ; accepted in final form 17 April 2006

Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure. Failing hearts are characterized by downregulation of -adrenergic receptor (-AR) signaling in part because of increased -AR kinase 1 activity. Our previous studies have shown that overexpression of the phosphoinositide kinase (PIK) domain of phosphoinositide 3-kinase (PI3K), prevents -AR downregulation and enhances adrenergic agonist responsiveness by inhibiting the targeting of PI3K to the -AR complex. To investigate whether preventing -AR downregulation in the heart ameliorates cardiac function post-MI, transgenic mice with cardiac-specific overexpression of the PIK domain peptide (TgPIK) underwent left coronary artery ligation and were subsequently followed by serial echocardiography at 4, 8, 12, 16, and 20 wk. Despite having similar infarction sizes, TgPIK mice showed better systolic function, less cardiac dilatation, and improved hemodynamic response to dobutamine compared with littermate controls after MI. To test that displacement of PI3K from the -AR complex, but not the total loss of PI3K-, is critical for amelioration of cardiac function, mice lacking the PI3K- (PI3K--KO) underwent MI, and their cardiac function was assessed 20 wk post-MI. Serial echocardiographic measurements showed severe reduction in contractile performance in PI3K--KO compared with TgPIK mice. Furthermore, significant -AR downregulation and desensitization were only seen in infarcted wild-type and PI3K--KO mice and not in TgPIK mice. Together, these results demonstrate that adverse remodeling of the ventricle after MI can be attenuated by a strategy that prevents recruitment of PI3K to the plasma membrane and restores normal -AR function.

heart failure; ventricular remodeling; transgenic models

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