Cardiac arrhythmias are the leading cause of death among heart failure (HF) patients. A growing body of evidence indicates that dysregulation in intracellular Ca2+ is a critical factor in these arrhythmias. Importantly, alterations in myocyte Ca2+ release are also widely considered the central player in the pathophysiology of heart failure. Specifically, HF myocytes display reduced sarcoplasmic reticulum (SR) Ca2+ stores and a reduction in SR Ca2+ transients. However, Ca2+-dependent arrhythmias (e.g., delayed after-depolarizations, DADs) are normally induced by SR Ca2+ overload. A critical, but unresolved question about heart failure is: how can Ca2+-dependent arrhythmias occur during HF, in a setting of globally decreased SR Ca2+ content? This paradox is poorly understood. Our long-term objective is to gain a mechanistic understanding of the Ca2+-dependent arrhythmias in HF. We recently observed striking remodeling of the t-tubule (TT) system and orphaned ryanodine receptors (RyRs) in cardiomyocytes isolated from spontaneously hypertensive rats (SHR) with overt HF. Based on our published and preliminary results, we hypothesize that during HF, TT structural remodeling plays an important mechanistic role in unstable Ca2+ homeostasis and therefore Ca2+-depedent arrhythmogenesis. Moreover, we predict that signaling pathways (e.g., PKA hyperphosphorylation and CaMKII upregulation) utilized by myocytes to compensate in response to primary insults may modulate TT remodeling. To test these hypotheses, we will address three specific aims:
Aim 1 - Evaluate the relationship between alterations in TT system and dysfunctional EC coupling in failing cardiomyocytes;
Aim 2 - Determine the role of TT remodeling in Ca2+-dependent arrhythmogenesis in HF;
Aim 3 - Define the role of CaMKII and PKA signaling in TT ultrastructural remodeling, abnormal Ca2+ signaling, and Ca2+-dependent arrhythmogenesis in HF models. To achieve these aims, we will combine state-of-the-art techniques, including patch-clamp (whole-cell, loose-sealed patch clamp);high-resolution confocal imaging;immunofluorescence;and digital image processing. We will use these techniques to examine isolated myocytes and intact hearts from mouse experimental HF models, including control and genetic mice in which phosphorylation is `globally'inhibited (AC3-I) or where specific CaMKII and PKA phosphorylation sites are disabled (RyR- S2814A, RyR-S2808A). We anticipate that fulfilling the proposed project will improve our understanding of the mechanisms underlying Ca2+-dependent arrhythmias and sudden cardiac death in human cardiomyopathies, and provide important insights into the development of effective therapeutic strategies for preventing and treating human HF and fatal cardiac arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090905-04
Application #
7995248
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
2007-12-15
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$375,000
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
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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