Mutations in the cardiac ryanodine receptor gene (RYR2) are associated with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), an arrhythmogenic syndrome characterized by the development of adrenergically-mediated ventricular tachycardia in individuals with an apparently normal heart. Very recently, point mutations in RYR2 have also been associated with Hypertrophic Cardiomyopathy (HCM), a major cause of sudden death where excessive cardiac mass leads to abnormalities in contraction, relaxation, conduction and rhythm. Hence, RyR2 mutations may lead to dysfunctional Ca2+ relsease, quite possibly the pivotal event for the initiation of tachyarrhythmias (CPVT) and/or pathological structural remodeling (HCM). However, while there has been some progress in the elucidation of the events that lead to CPVT, the molecular and cellular mechanisms that link a RyR2 mutation with the development of HCM are completely unknown. Hypothesis: we propose that RyR2- originated CPVT and HCM phenotypes arise from distinct mechanisms of channel dysfunction, the severity of which is commensurate with the hierarchy of the affected domain in the control of Ca2+ release. CPVT mutations cluster in domains that rev up RyR2 activity under -sympathetic stimulation, are normally silent, and throw RyR2 channels into catastrophic Ca2+ release under conditions of stress, leading to tachyarrhythmias; HCM mutations, on the other hand, fall in domains that control basal RyR2 activity, elicit chronic and insidious Ca2+ release due to constitutive activation of RyR2 channels, and lead to pathological cardiac remodeling. Our general aim is to determine the molecular and cellular mechanisms underlying HCM due to RyR2 dysfunction. We have generated a transgenic mouse that harbors a RyR2 mutation (RyR2-P1124L) associated with HCM in humans. Mice heterozygous for the mutation (RyR2-P1124L+/-) recapitulate the cardinal signs of HCM, including chamber remodeling, cellular hypertrophy, and increased propensity for arrhythmias. We will use a combination of molecular, cellular and whole heart studies to elucidate the fundamental mechanisms by which RyR2 dysfunction triggers HCM.
Aim 1 will determine the molecular mechanisms by which the RyR2-P1124L mutation gives rise to HCM.
Aim 2 will determine the cellular mechanisms by which the RyR2-P1124L mutation gives rise to HCM.
Aim 3 will determine the signaling pathways that induce cardiac hypertrophy and arrhythmogenesis in RyR2-P1124L+/- mice. The proposed experimental design is therefore highly innovative and will be carried out with an unprecedented level of integrative physiology.

Public Health Relevance

Mutations in the cardiac ryanodine receptor gene (RYR2) are linked to Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and may trigger life-threatening arrhythmias. Here we show that RYR2 mutations in domains different to those leading to CPVT can trigger arrhythmogenic Hypertrophic Cardiomyopathy (HCM) in mice and humans. These novel findings not only uncover fundamental knowledge on the structure-function relationship of RyR2 proteins, but also offer a completely novel paradigm for investigation of HCM pathogenesis. The results may open new therapeutic avenues for a subset of HCM patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055438-20
Application #
9243283
Study Section
Special Emphasis Panel (ZRG1-CVRS-B (02))
Program Officer
Lathrop, David A
Project Start
1996-03-08
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
20
Fiscal Year
2017
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Vargas-Jaimes, Leonel; Xiao, Liang; Zhang, Jing et al. (2017) Recombinant expression of Intrepicalcin from the scorpion Vaejovis intrepidus and its effect on skeletal ryanodine receptors. Biochim Biophys Acta 1861:936-946
Alvarado, Francisco J; Chen, Xi; Valdivia, Héctor H (2017) Ablation of the cardiac ryanodine receptor phospho-site Ser2808 does not alter the adrenergic response or the progression to heart failure in mice. Elimination of the genetic background as critical variable. J Mol Cell Cardiol 103:40-47
Bao, Yangyang; Willis, B Cicero; Frasier, Chad R et al. (2016) Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. Circ Arrhythm Electrophysiol 9:
Wu, Yuejin; Valdivia, Héctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180
Helms, Adam S; Alvarado, Francisco J; Yob, Jaime et al. (2016) Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy. Circulation 134:1738-1748
Marmugi, Alice; Parnis, Julia; Chen, Xi et al. (2016) Sorcin Links Pancreatic ?-Cell Lipotoxicity to ER Ca2+ Stores. Diabetes 65:1009-21
Xiao, Liang; Gurrola, Georgina B; Zhang, Jing et al. (2016) Structure-function relationships of peptides forming the calcin family of ryanodine receptor ligands. J Gen Physiol 147:375-94
Willis, B Cicero; Pandit, Sandeep V; Ponce-Balbuena, Daniela et al. (2016) Constitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation 133:2348-59
Zhao, Yan-Ting; Valdivia, Carmen R; Gurrola, Georgina B et al. (2015) Arrhythmogenic mechanisms in ryanodine receptor channelopathies. Sci China Life Sci 58:54-8
Valdivia, Héctor H (2015) Mechanisms of cardiac alternans in atrial cells: intracellular Ca2? disturbances lead the way. Circ Res 116:778-80

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