Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice
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
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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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 6

Ultrastructural morphology of cardiomyocytes and mitochondrial defects in 9-month-old CFKO mice.

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Ultrastructural morphology of cardiomyocytes and mitochondrial defects i...
Representative transmission electron micrographs of ventricle specimens from control (A, C, and E) and CFKO (B, D, and F) mice. Well-organized myofibrils (arrows) with mitochondria (m) grouped along the periphery of longitudinally oriented fibers are found in control mice (A), whereas myofibrillar disarray as well as pronounced increases in nonmyofibrillar space filled with mitochondria arranged in aggregates disorganizing fibrils were evident in CFKO mice (B). Mitochondria have tightly packed, intact horizontally oriented cristae in control mice (C), while in CFKO mice, the mitochondria are swelled, the affected mitochondrial cristae are no longer regular and horizontal, and their matrix is partially lucent and irregularly spaced (D). Well-preserved intercalated disk with smooth contours in control mice (E) and affected straighter intercalated disk with unusual sharp angles in CFKO mice (F). Magnification, ×7,000 (scale bars: 1 μm; A and B) and ×30,000 (scale bars: 500 nm; C–F).