Cardiomyocyte-Specific Expression of CRNK, the C-terminal Domain of PYK2, Maintains Ventricular Function and Slows Ventricular Remodeling in a Mouse Model of Dilated Cardiomyopathy Journal Article

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Authors: Koshman, Y. E.; Chu, M.; Kim, T.; Kalmanson, O.; Farjah, M.; Kumar, M; Lewis, W.; Geenen, D. L.; De Tombe, P; Goldspink, P. H.; John Solaro, R.; Samarel, A. M.
Article Title: Cardiomyocyte-Specific Expression of CRNK, the C-terminal Domain of PYK2, Maintains Ventricular Function and Slows Ventricular Remodeling in a Mouse Model of Dilated Cardiomyopathy
Abstract: RATIONALE: Up-regulation and activation of PYK2, a member of the FAK family of protein tyrosine kinases, is involved in the pathogenesis of left ventricular (LV) remodeling and heart failure (HF). PYK2 activation can be prevented by CRNK, the C-terminal domain of PYK2. We previously demonstrated that adenoviral-mediated CRNK gene transfer improved survival and LV function, and slowed LV remodeling in a rat model of coronary artery ligation-induced HF. OBJECTIVE: We now interrogate whether cardiomyocyte-specific, transgenic CRNK expression prevents LV remodeling and HF in a mouse model of dilated cardiomyopathy (DCM) caused by constitutively active Protein Kinase Cepsilon (caPKCepsilon). METHODS AND RESULTS: Transgenic (TG; FVB/N background) mice were engineered to express rat CRNK under control of the alpha-myosin heavy chain promoter, and crossed with FVB/N mice with cardiomyocyte-specific expression of caPKCepsilon to create double TG mice. LV structure, function, and gene expression was evaluated in all 4 groups (nonTG FVB/N; caPKCepsilon(+/-); CRNK(+/-); and caPKCepsilon x CRNK (PXC) double TG mice) at 1, 3, 6, 9 and 12mo of age. CRNK expression followed a Mendelian distribution, and CRNK mice developed and survived normally through 12mo. Cardiac structure, function and selected gene expression of CRNK mice were similar to nonTG littermates. CRNK had no effect on caPKCepsilon expression and vice versa. PYK2 was up-regulated ~6-fold in caPKCepsilon mice, who developed a non-hypertrophic, progressive DCM with reduced systolic (Contractility Index=151+/-5 vs. 90+/-4 sec-1) and diastolic (Tau=7.5+/-0.5 vs. 14.7+/-1.3 msec) function, and LV dilatation (LV Remodeling Index (LVRI)=4.2+/-0.1 vs. 6.0+/-0.3 for FVB/N vs. caPKCepsilon mice, respectively; P0.05 for each at 12mo). In double TG PXC mice, CRNK expression significantly prolonged survival, improved contractile function (Contractile Index=115+/-8 sec-1; Tau=9.5+/-1.0 msec), and reduced LV remodeling (LVRI=4.9+/-0.1). CONCLUSIONS: Cardiomyocyte-specific expression of CRNK improves contractile function and slows LV remodeling in a mouse model of DCM.
Journal Title: Journal of Molecular and Cellular Cardiology
Volume: 72C
ISSN: 1095-8584; 0022-2828
Publisher: Elsevier Inc  
Date Published: 2014
Start Page: 281
End Page: 291
Language: ENG
DOI/URL:

10.1016/j.yjmcc.2014.03.021

10.1016/j.yjmcc.2014.03.021
Notes: CI: Copyright (c) 2014; JID: 0262322; OTO: NOTNLM; 2013/10/11 [received]; 2014/02/22 [revised]; 2014/03/29 [accepted]; aheadofprint