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
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Zhang, Caimei; Chen, Biyi; Guo, Ang et al. (2014) Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation 129:1742-50
Zhu, Zhiyong; Sierra, Ana; Burnett, Colin M-L et al. (2014) Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. J Gen Physiol 143:119-34
Guo, Ang; Zhang, Xiaoying; Iyer, Venkat Ramesh et al. (2014) Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress. Proc Natl Acad Sci U S A 111:12240-5
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