The overall goal of this proposal is to understand the role of altered intracellular Ca handling in the pathophysiology of heart failure. The proposal focuses on a recently discovered abnormality in the function of the sarcoplasmic reticulum (SR) Ca release channel (also known as the cardiac ryanodine receptor, RyR2) that makes the RyR2 overly active, i.e. """"""""leaky"""""""" for Ca. In HF, the RyR2 becomes leaky due to abnormal modulation of the channel by Ca from inside the SR, a mechanism that normally operates to facilitate the transition of the RyR2s into a refractory state following SR Ca release. RyR2 luminal Ca regulation involves cooperation of several proteins associated with the RyR2 from the luminal side, including triadin 1, junctin and calsequestrin. Increased RyR2 activity would lead to Ca depletion in the SR, reducing Ca available for contraction, potentially contributing to the weakened cardiac contractile force in HF. Additionally, a sustained Ca leak might be capable of activating Ca dependent kinases and phosphatases that can feed back on RyR2s to cause more leak and a further derangement of the Ca release machinery. A comprehensive research plan is proposed to define the specific molecular causes responsible for this RyR2 dysfunction and its role in abnormal Ca handling of failing myocytes and in the natural development of HF. Our studies will use a unique combination of in vivo techniques and methods of cellular and molecular physiology, including patch clamp measurements, Ca imaging in the cytosolic and SR compartments and recording from single reconstituted RyR2 channels. We will use a large animal model of chronic HF which is highly relevant to human HF. The specific questions that will be addressed in this research proposal include: 1) What are the relative roles of altered SERCA2-mediated uptake, reduced NCX removal and enhanced SR Ca leak in altered Ca handling;2) Can the defective Ca homeostasis of failing myocytes be normalized by RyR2 inhibitors or by genetically targeting regulatory proteins involved in RyR2 luminal Ca-dependent modulation;3) Is abnormal RyR2 gating behavior is caused by abnormal phosphorylation/dephosphorylation of the RyR2 and/or by altered interactions with luminal auxiliary proteins involved in luminal Ca sensing;4) Is abnormal Ca handling a cause or a consequence of HF;and 5) Does transition to end stage HF involve an enhanced RyR leak, and do therapeutic interventions such as cardiac resynchronization therapy act by normalizing abnormal RyR2 function.

Public Health Relevance

Heart failure occurs when the heart is unable to pump enough blood to meet the needs of the body. Heart failure continues to increase in the U.S. population and is the most common diagnosis in hospitalized patients over the age of 65. We propose to study how abnormalities in the regulation of calcium in the heart muscle contribute to heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074045-09
Application #
7806525
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2003-07-01
Project End
2011-10-30
Budget Start
2010-05-01
Budget End
2011-10-30
Support Year
9
Fiscal Year
2010
Total Cost
$375,000
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Györke, Sándor; Belevych, Andriy E; Liu, Bin et al. (2017) The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis. J Gen Physiol 149:877-888
Ho, Hsiang-Ting; Thambidorai, Senthil; Knollmann, Björn C et al. (2017) Accentuated vagal antagonism paradoxically increases ryanodine receptor calcium leak in long-term exercised Calsequestrin2 knockout mice. Heart Rhythm :
Belevych, Andriy E; Ho, Hsiang-Ting; Bonilla, Ingrid M et al. (2017) The role of spatial organization of Ca2+ release sites in the generation of arrhythmogenic diastolic Ca2+ release in myocytes from failing hearts. Basic Res Cardiol 112:44
Ho, Hsiang-Ting; Belevych, Andriy E; Liu, Bin et al. (2016) Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II. Hypertension 68:1171-1178
Shettigar, Vikram; Zhang, Bo; Little, Sean C et al. (2016) Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Nat Commun 7:10794
Radwa?ski, Przemys?aw B; Ho, Hsiang-Ting; Veeraraghavan, Rengasayee et al. (2016) Neuronal Na+Channels Are Integral Components of Pro-arrhythmic Na+/Ca2+Signaling Nanodomain That Promotes Cardiac Arrhythmias During ?-adrenergic Stimulation. JACC Basic Transl Sci 1:251-266
Liu, Bin; Ho, Hsiang-Ting; Brunello, Lucia et al. (2015) Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT. Cardiovasc Res 108:299-311
Radwa?ski, Przemys?aw B; Brunello, Lucia; Veeraraghavan, Rengasayee et al. (2015) Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release. Cardiovasc Res 106:143-52
Long 3rd, Victor P; Bonilla, Ingrid M; Vargas-Pinto, Pedro et al. (2015) Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci 123:61-71
Roof, Steve R; Ho, Hsiang-Ting; Little, Sean C et al. (2015) Obligatory role of neuronal nitric oxide synthase in the heart's antioxidant adaptation with exercise. J Mol Cell Cardiol 81:54-61

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