title: Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress.
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.
authors.affiliation: 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;
authors.forename: Ang
authors.initials: A
authors.lastname: Guo
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140;
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19140; and.
authors.forename: Venkat Ramesh
authors.initials: VR
authors.lastname: Iyer
authors.affiliation: 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;
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Caimei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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;
authors.forename: William J
authors.initials: WJ
authors.lastname: Kutschke
authors.affiliation: 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;
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104 long-sheng-song@uiowa.edu armstroc@mail.med.upenn.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Franzini-Armstrong
authors.affiliation: 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.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D013312:Stress, Physiological; D017725:Ventricular Pressure
chemical_list: D002118:Calcium; D008565:Membrane Proteins; D009124:Muscle Proteins; C000589042:JP2 protein, mouse
keywords: cardiac dyads; electron microscopy; in situ Ca2+ imaging
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