Despite advances in the understanding of underlying mechanisms, heart failure (HF) remains the major cause of mortality, indicating the urgent need in the development of novel unconventional therapeutic strategies. Abnormal intracellular calcium (Ca2+) handling has been implicated in the pathogenesis of malignant arrhythmias characteristic of Heart Failure (HF). Cardiac excitation-contraction (EC) coupling is mediated through Ca2+-induced Ca2+ release (CICR), which is controlled by sarcoplasmic reticulum (SR) Ca2+-sensitive Ca2+ channels, also known as cardiac ryanodine receptors (RyR2). MicroRNAs (miRs) are ~22-nucleotide-long nonprotein-coding RNAs that recognize their target mRNAs by base pairing interactions and subsequently inhibit gene expression by targeting these mRNAs for translational repression or degradation. Rapidly accumulating evidence implicates dysregulated miRs in cardiac pathogenesis including arrhythmias and HF rendering them new attractive targets for therapy. However, much work must be done for better understanding of miR functions. Our preliminary results implicate a family of miRs specific to muscle tissue called myomiRs in regulation of Ca2+ handling in cardiomyocytes. The central hypothesis of this proposal is that myomiRs which include miR-208a, miR-208b and miR-499 play a critical role in regulating Ca2+ homeostasis by modulating the structure and function of macromolecular complexes involved in Ca2+ handling. In order to test this hypothesis we have developed techniques to modify the expression of miRNAs in vitro and in intact hearts in vivo in order to examine their effects on Ca2+ cycling in single ventricular myocytes using electrophysiology and single photon laser scanning confocal microscopy. Specifically we aim to investigate the molecular determinants of myomiR-mediated regulation of SR Ca2+ release through RyR2s in ventricular myocytes, and test whether aberrant expression patterns of these miRs contribute to Ca2+-dependent arrhythmias characteristic of cardiac disease using rat model of heart failure.

Public Health Relevance

MicroRNAs, recently discovered class of posttranscriptional regulators of gene expression, have been implicated in cardiac pathology including malignant cardiac arrhythmia and heart failure. MicroRNAs are thought to have a significant therapeutic potential due to their ability to regulate multiple functionally associated genes. These studies into modulation of cardiomyocyte function by a group of microRNAs specific to muscle tissue called myomiRs should contribute important insights into mechanisms of arrhythmia and contractile dysfunction associated with acquired cardiac disorders and assist in development of informed microRNA-based therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121796-05
Application #
9607616
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2014-11-14
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
Choi, Bum-Rak; Li, Weiyan; Terentyev, Dmitry et al. (2018) Transient Outward K+ Current (Ito) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1. Circ Arrhythm Electrophysiol 11:e005414
Zhong, Mingwang; Rees, Colin M; Terentyev, Dmitry et al. (2018) NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes. Biophys J 115:1019-1032
Allawzi, Ayed M; Vang, Alexander; Clements, Richard T et al. (2018) Activation of Anoctamin-1 Limits Pulmonary Endothelial Cell Proliferation via p38-Mitogen-activated Protein Kinase-Dependent Apoptosis. Am J Respir Cell Mol Biol 58:658-667
Chorzalska, Anna; Kim, Javier Flores; Roder, Karim et al. (2017) Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia. Stem Cells Dev 26:656-677
Kim, Tae Yun; Terentyeva, Radmila; Roder, Karim H F et al. (2017) SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. Cardiovasc Res 113:343-353
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
Terentyev, Dmitry; Hamilton, Shanna (2016) Regulation of sarcoplasmic reticulum Ca2+ release by serine-threonine phosphatases in the heart. J Mol Cell Cardiol 101:156-164
Clements, Richard T; Terentyev, Dmitry; Sellke, Frank W (2015) Ca(2+)-activated K(+) channels as therapeutic targets for myocardial and vascular protection. Circ J 79:455-62
Cordeiro, Brenda; Terentyev, Dmitry; Clements, Richard T (2015) BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion. Am J Physiol Heart Circ Physiol 309:H625-33