Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice
Xu Peng, … , Hua Gu, Jun-Lin Guan
Xu Peng, … , Hua Gu, Jun-Lin Guan
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):217-227. https://doi.org/10.1172/JCI24497.
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Research Article Cardiology

Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice

Abstract

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.

Authors

Xu Peng, Marc S. Kraus, Huijun Wei, Tang-Long Shen, Romain Pariaut, Ana Alcaraz, Guangju Ji, Lihong Cheng, Qinglin Yang, Michael I. Kotlikoff, Ju Chen, Kenneth Chien, Hua Gu, Jun-Lin Guan

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Figure 1

Ventricular cardiomyocyte–specific deletion of FAK.

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Ventricular cardiomyocyte–specific deletion of FAK. (A) Schematics of FA...
(A) Schematics of FAK WT, floxed, and deleted (Δ) alleles. Large filled triangles represent loxP sites. Horizontal lines with arrows indicate the expected sizes of DNA bands in Southern blotting of the floxed and Δ alleles. Horizontal lines with filled diamonds indicate the expected sizes of DNA bands in PCR. The location of the SacI (S) restriction sites and the primers P1 and P2 (arrows) are shown. E3, exon 3. (B) Genomic DNA from different tissues of CFKO mice were amplified by PCR with DNA from tails of various control mice (3 left lanes) as controls. The DNA bands corresponding to the flox, WT, and Δ alleles are marked on the left. SK, skeletal muscle. (C) Southern blotting analysis of the genomic DNA from lungs and ventricles of control (lane 1) and CFKO (lane 2) mice after SacI digestion. The positions of floxed and Δ alleles are marked on the right. (D) Lysates were prepared from ventricles of control and CFKO mice at different time points, as indicated. They were then analyzed by Western blotting using various antibodies, as indicated. (E and F) Lysates were prepared from LV, RV, or isolated cardiomyocytes from control and CFKO mice, as indicated. They were then analyzed by Western blotting using various antibodies, as indicated.