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(Circulation. 2009;120:568-576.)
© 2009 American Heart Association, Inc.

Heart Failure

Targeted Ablation of PINCH1 and PINCH2 From Murine Myocardium Results in Dilated Cardiomyopathy and Early Postnatal Lethality

Xingqun Liang, MD, PhD^*; Yunfu Sun, MD, PhD^*; Maoqing Ye, MD, PhD^*; Maria C. Scimia, MD; Hongqiang Cheng, PhD; Jody Martin, PhD; Gang Wang, PhD; Ann Rearden, MD; Chuanyue Wu, PhD; Kirk L. Peterson, MD; Henry C. Powell, MD; Sylvia M. Evans, PhD; Ju Chen, PhD

From Department of Medicine (X.Q.L., Y.F.S., M.C.S., H.Q.C., J.M., G.W., K.L.P., S.M.E., J.C.), School of Pharmacology (Y.F.S., J.M., G.W., S.M.E.), Department of Pediatrics (M.Q.Y.), and Department of Pathology (A.R., H.C.P.), University of California at San Diego, and Department of Pathology, University of Pittsburgh, Pittsburgh, Pa (C.Y.W.).

Correspondence to Ju Chen, PhD, Department of Medicine, University of California at San Diego, 9500 Gilman Dr, La Jolla, CA 92093–0613. E-mail juchen{at}ucsd.edu

Received March 12, 2009; accepted June 1, 2009.

Background— PINCH proteins are 5 LIM domain–only adaptor proteins that function as key components of the integrin signaling pathway and play crucial roles in multiple cellular processes. Two PINCH proteins, PINCH1 and PINCH2, have been described in mammals and share high homology. Both PINCH1 and PINCH2 are ubiquitously expressed in most tissues and organs, including myocardium. Cardiac-specific PINCH1 knockout or global PINCH2 knockout mice exhibit no basal cardiac phenotype, which may reflect a redundant role for these 2 PINCH proteins in myocardium. A potential role for PINCH proteins in myocardium remains unknown.

Methods and Results— To define the role of PINCH in myocardium, we generated mice that were doubly homozygous null for PINCH1 and PINCH2 in myocardium. Resulting mutants were viable at birth but developed dilated cardiomyopathy and died of heart failure within 4 weeks. Mutant hearts exhibited disruptions of intercalated disks and costameres accompanied by fibrosis. Furthermore, multiple cell adhesion proteins exhibited reduced expression and were mislocalized. Mutant cardiomyocytes were significantly smaller and irregular in size. In addition, we observed that the absence of either PINCH1 or PINCH2 in myocardium leads to exacerbated cardiac injury and deterioration in cardiac function after myocardial infarction.

Conclusions— These results demonstrate essential roles for PINCHs in myocardial growth, maturation, remodeling, and function and highlight the importance of studying the role of PINCHs in human cardiac injury and cardiomyopathy.

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