Junctophilin 2 (JP2) is a structural protein required for the formation of junctional couplings (i.e., cardiac dyads) between transverse (T)-tubule membrane and sarcoplasmic reticulum (SR) and is fundamental for local control of Ca2+-induced Ca2+ release and efficient contraction in ventricular myocytes during cardiac excitation- contraction (E-C) coupling. In animal models of heart failure, JP2 protein levels progressively decline, leading to T-tubule remodeling and loss of E-C coupling function. JP2 levels are also markedly reduced in human failing hearts. Our recently published and preliminary data demonstrate that JP2 is posttranslational regulated by calpain, a Ca2+-activated protease implicated in a variety of heart diseases. JP2 cleavage by calpain was originally hypothesized to underlie JP2 downregulation in failing hearts. In pilot studies, we made the novel and unexpected observation that an N-terminal JP2 cleavage fragment, termed JP2NT, unlike full length JP2, is imported into nucleus, where it has a profound function in transcriptional reprogramming in cardiomyocytes. However, the (patho) physiological consequences of JP2NT nuclear localization and related molecular mechanisms are completely unknown. Based on these novel exciting preliminary findings, we hypothesize that, in response to stress, calpain-mediated cleavage of JP2 transforms JP2 from a structural protein into a transcriptional regulator that reprograms the transcriptional profile of damaged cardiomyocytes and represses the development of cardiac hypertrophy. This molecular event may be an important trigger for transcriptional remodeling, serving as an unappreciated protective mechanism under pathological conditions. We will test our hypothesis using a multidisciplinary approach, including multiple novels transgenic and CRISPR-based mouse models, molecular biology, biochemistry and a novel in situ confocal imaging technique developed by our lab.
In Aim 1, we will explore the molecular mechanisms underlying JP2NT transcriptional regulation in cardiomyocytes, whereas Aim 2 will examine the patho(physiological) consequences of JP2NT in the heart. We anticipate the proposed studies will provide significant insights into the novel functions of JP2NT in membrane-to-nucleus signal transduction in the setting of cardiac stress and new insights into the cross- communication between cardiomyocyte structural remodeling and transcriptional remodeling in heart disease. This information will serve as a platform for the future development of novel heart failure therapeutics.

Public Health Relevance

Heart failure is the most common cause of hospitalization in patients over 65 and causes an enormous burden on our health care system. New therapeutic approaches for heart failure are still critically needed. Our studies will likely reveal novel insihts into the function of the truncated form of structural protein Junctophilin-2 in heart failure, and shed light on future development of novel heart failure therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130346-02
Application #
9199431
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
2016-01-15
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Guo, Ang; Chen, Rong; Wang, Yihui et al. (2018) Transient activation of PKC results in long-lasting detrimental effects on systolic [Ca2+]i in cardiomyocytes by altering actin cytoskeletal dynamics and T-tubule integrity. J Mol Cell Cardiol 115:104-114
Chiamvimonvat, Nipavan; Song, Long-Sheng (2018) LRRC10 (Leucine-Rich Repeat Containing Protein 10) and REEP5 (Receptor Accessory Protein 5) as Novel Regulators of Cardiac Excitation-Contraction Coupling Structure and Function. J Am Heart Assoc 7:
Guo, Ang; Wang, Yihui; Chen, Biyi et al. (2018) E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science 362:
Wang, Yihui; Chen, Biyi; Huang, Chun-Kai et al. (2018) Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models. JACC Basic Transl Sci 3:503-517
Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K et al. (2018) Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ Res 122:821-835
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Zhang, Caimei; Chen, Biyi; Wang, Yihui et al. (2017) MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress. J Mol Cell Cardiol 112:123-130
Arora, Rishi; Aistrup, Gary L; Supple, Stephen et al. (2017) Regional distribution of T-tubule density in left and right atria in dogs. Heart Rhythm 14:273-281
Hall, Duane D; Ponce, Jessica M; Chen, Biyi et al. (2017) Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure. JCI Insight 2:
Guo, Yuxuan; VanDusen, Nathan J; Zhang, Lina et al. (2017) Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo. Circ Res 120:1874-1888

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