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Author Notes:

Allen M. Samarel, M.D., The Cardiovascular Institute, Building 110, Rm 5222, 2160 South First Avenue, Maywood, IL 60153, V: 708-327-2829, F: 708-327-2849, asamare@lumc.edu.

Authors reported no disclosures.

Subjects:

Research Funding:

Supported by NIH P01 HL62426; R01 DA030996; R01 HL75494; and F32 HL096143.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Cell Biology
  • Cardiovascular System & Cardiology
  • Heart failure
  • Gene expression
  • Protein kinase C
  • Echocardiography
  • Focal adhesion kinase
  • PROTEIN-KINASE-C
  • FOCAL ADHESION KINASE
  • SARCO(ENDO)PLASMIC RETICULUM CA2+-ATPASE
  • DEPENDENT TYROSINE KINASE
  • SERCA2 GENE-EXPRESSION
  • CONTRACTILE DYSFUNCTION
  • IMPROVES FUNCTION
  • HEART-FAILURE
  • ACTIVATION
  • PHOSPHORYLATION

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

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Journal Title:

Journal of Molecular and Cellular Cardiology

Volume:

Volume 72

Publisher:

, Pages 281-291

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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. 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 Cε (caPKCε). Transgenic (TG; FVB/N background) mice were engineered to express rat CRNK under control of the α-myosin heavy chain promoter, and crossed with FVB/N mice with cardiomyocyte-specific expression of caPKCε to create double TG mice. LV structure, function, and gene expression were evaluated in all 4 groups (nonTG FVB/N; caPKCε(+/-); CRNK(+/-); and caPKCε×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 caPKCε expression and vice versa. PYK2 was up-regulated ~6-fold in caPKCε mice, who developed a non-hypertrophic, progressive DCM with reduced systolic (Contractility Index=151±5 vs. 90±4s-1) and diastolic (Tau=7.5±0.5 vs. 14.7±1.3ms) function, and LV dilatation (LV Remodeling Index (LVRI)=4.2±0.1 vs. 6.0±0.3 for FVB/N vs. caPKCε mice, respectively; P<0.05 for each at 12mo). In double TG PXC mice, CRNK expression significantly prolonged survival, improved contractile function (Contractile Index=115±8s-1; Tau=9.5±1.0ms), and reduced LV remodeling (LVRI=4.9±0.1). Cardiomyocyte-specific expression of CRNK improves contractile function and slows LV remodeling in a mouse model of DCM.

Copyright information:

© 2014 Elsevier Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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