Heart failure (HF), the fastest-growing type of cardiac disease in the U.S., is a pathophysiologic state in which the heart fails to pump sufficient blood to meet the needs of the body. In failing ventricular myocytes from animal models and human patients, we and others have demonstrated disruption of the widely distributed and highly organized cardiomyocyte traverse (T)-tubule system. These orderly invaginations of surface membrane into the cell interior are critical for rapid electric excitation, initiation and synchronus triggering of sarcoplasmic reticulum (SR) Ca2+ release, and, therefore, coordinated contraction of each contractile unit throughout the entire myocyte. T-tubule loss and disorganization instigate development of HF due to aberrant intracellular Ca2+ release and blunted contractile function. However, there is a limited understanding of the molecular mechanisms and pathways that regulate T-tubular integrity or that participate in destructive T-tubule remodeling. Our preliminary data indicate that junctophilin-2 (JP2), a structural protein spanning T-tubules and the SR membrane, is crucial for normal T-tubule organization. Our data in animal models of cardiac stress show that downregulation of the JP2 is associated with T-tubule disorganization and HF development. Furthermore, our preliminary results indicate that JP2 downregulation is driven by activation of the Ca2+- dependent protease, calpain, though the upstream events that result in calpain-mediated degradation of JP2 in HF remain unclear. The goal of this project is to define the mechanisms of JP2 dysregulation and T-tubule remodeling in cardiac disease. We will combine multidisciplinary approaches including in situ confocal imaging, electrophysiology, molecular biology, pathological mouse models and novel transgenic mouse models, to test two specific aims.
Aim 1. To define the molecular mechanisms underlying JP2 downregulation in heart failure.
Aim 2. To determine if and how recombinant JP2 expression can attenuate stress-induced T-tubule remodeling and protect against HF progression. As HF 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 HF are still critically needed. The potential positive impact of these studies is that preventing T-tubule dysfunction may represent a novel mechanism-based approach to improve health care outcomes related to HF. Understanding these molecular mechanisms will provide a novel platform for T-tubule-targeted therapies that prevent HF development and progression.

Public Health Relevance

As 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 HF are still critically needed. The potential positive impact of these studies is that preventing T-tubule dysfunction may represent a novel mechanism-based approach to improve health care outcomes related to heart failure. Understanding these molecular mechanisms will provide a novel platform for T-tubule-targeted therapies that prevent heart failure development and progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL090905-06
Application #
8437945
Study Section
Special Emphasis Panel (ZRG1-CVRS-E (02))
Program Officer
Krull, Holly
Project Start
2007-12-15
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$359,380
Indirect Cost
$121,380
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
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
Huang, Chun-kai; Chen, Bi-yi; Guo, Ang et al. (2016) Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model. Acta Pharmacol Sin 37:473-82

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