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Peng, X, Kraus, MS, Wei, H, Shen, TL, Pariaut, R, Alcaraz, A, Ji, G, Cheng, L, Yang, Q, Kotlikoff, MI, Chen, J, Chien, K, Gu, H and Guan, JL (2006) Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J. Clin. Invest. 116:217-27
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a major role in integrin signaling pathways. Although cardiovascular defects were observed in FAK total KO mice, the embryonic lethality prevented investigation of FAK function in the hearts of adult animals. To circumvent these problems, we created mice in which FAK is selectively inactivated in cardiomyocytes (CFKO mice). We found that CFKO mice develop eccentric cardiac hypertrophy (normal LV wall thickness and increased left chamber dimension) upon stimulation with angiotensin II or pressure overload by transverse aortic constriction as measured by echocardiography. We also found increased heart/body weight ratios, elevated markers of cardiac hypertrophy, multifocal interstitial fibrosis, and increased collagen I and VI expression in CFKO mice compared with control littermates. Spontaneous cardiac chamber dilation and increased expression of hypertrophy markers were found in the older CFKO mice. Analysis of cardiomyocytes isolated from CFKO mice showed increased length but not width. The myocardium of CFKO mice exhibited disorganized myofibrils with increased nonmyofibrillar space filled with swelled mitochondria. Last, decreased tyrosine phosphorylation of FAK substrates p130Cas and paxillin were observed in CFKO mice compared with the control littermates. Together, these results provide strong evidence for a role of FAK in the regulation of heart hypertrophy in vivo.
Animals; Base Sequence; Blotting, Northern; Cardiomegaly/pathology; DNA Primers; Fibrosis; Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases/deficiency; Focal Adhesion Protein-Tyrosine Kinases/genetics; Mice; Mice, Knockout; Muscle Cells/enzymology; Myocardium/enzymology; Myocardium/pathology; Polymerase Chain Reaction
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