Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress

Ang Guo; Xiaoying Zhang; Venkat Ramesh Iyer; Biyi Chen; Caimei Zhang; William J Kutschke; Robert M Weiss; Clara Franzini-Armstrong; Long-Sheng Song

doi:10.1073/pnas.1412729111

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Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress

Journal article

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Peer reviewed

Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress

Ang Guo, Xiaoying Zhang, Venkat Ramesh Iyer, Biyi Chen, Caimei Zhang, William J Kutschke, Robert M Weiss, Clara Franzini-Armstrong and Long-Sheng Song

Proceedings of the National Academy of Sciences - PNAS, Vol.111(33), pp.12240-12245

08/19/2014

DOI: 10.1073/pnas.1412729111

PMCID: PMC4143026

PMID: 25092313

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Abstract

Heart failure is accompanied by a loss of the orderly disposition of transverse (T)-tubules and a decrease of their associations with the junctional sarcoplasmic reticulum (jSR). Junctophilin-2 (JP2) is a structural protein responsible for jSR/T-tubule docking. Animal models of cardiac stresses demonstrate that down-regulation of JP2 contributes to T-tubule disorganization, loss of excitation-contraction coupling, and heart failure development. Our objective was to determine whether JP2 overexpression attenuates stress-induced T-tubule disorganization and protects against heart failure progression. We therefore generated transgenic mice with cardiac-specific JP2 overexpression (JP2-OE). Baseline cardiac function and Ca(2+) handling properties were similar between JP2-OE and control mice. However, JP2-OE mice displayed a significant increase in the junctional coupling area between T-tubules and the SR and an elevated expression of the Na(+)/Ca(2+) exchanger, although other excitation-contraction coupling protein levels were not significantly changed. Despite similar cardiac function at baseline, overexpression of JP2 provided significantly protective benefits after pressure overload. This was accompanied by a decreased percentage of surviving mice that developed heart failure, as well as preservation of T-tubule network integrity in both the left and right ventricles. Taken together, these data suggest that strategies to maintain JP2 levels can prevent the progression from hypertrophy to heart failure.

Animals

Calcium - metabolism

Heart Failure - physiopathology

Muscle Proteins - metabolism

Stress, Physiological

Myocytes, Cardiac - metabolism

Mice, Transgenic

Heart Failure - metabolism

Membrane Proteins - metabolism

Mice

Ventricular Pressure

Details

Title: Subtitle: Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress
Creators: Ang Guo - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Xiaoying Zhang - Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140
Venkat Ramesh Iyer - Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19140; and
Biyi Chen - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Caimei Zhang - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
William J Kutschke - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Robert M Weiss - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Clara Franzini-Armstrong - Department of Cell and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104 long-sheng-song@uiowa.edu armstroc@mail.med.upenn.edu
Long-Sheng Song - Division of Cardiovascular Medicine, Department of Internal Medicine, and Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242; long-sheng-song@uiowa.edu armstroc@mail.med.upenn.edu
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.111(33), pp.12240-12245
DOI: 10.1073/pnas.1412729111
PMID: 25092313
PMCID: PMC4143026
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: R01 HL48093 / NHLBI NIH HHS R01 HL048093 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS
Language: English
Date published: 08/19/2014
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094403502771

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