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 #
5R01HL121796-02
Application #
8962163
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
2015-11-01
Budget End
2016-10-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
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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