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Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility.

AbstractAIMS:
Impaired sarcoplasmic reticulum (SR) Ca(2+) cycling and depressed contractility, a hallmark of human and experimental heart failure, has been partially attributed to increased protein phosphatase 1 (PP-1) activity, associated with down-regulation of its endogenous inhibitor-1. The levels and activity of inhibitor-1 are reduced in failing hearts, contributing to dephosphorylation and inactivation of key calcium cycling proteins. Therefore, we investigated the mechanisms that mediate decreases in inhibitor-1 by post-transcriptional modification.
METHODS AND RESULTS:
Bioinformatics revealed that 17 human microRNAs may serve as modulators of inhibitor-1. However, real-time PCR analysis identified only one of these microRNAs, miR-765, as being increased in human failing hearts concomitant with decreased inhibitor-1 levels. Expression of miR-765 in HEK293 cells or mouse ventricular myocytes confirmed suppression of inhibitor-1 levels through binding of this miR-765 to the 3'-untranslated region of inhibitor-1 mRNA. To determine the functional significance of miR-765 in Ca(2+) cycling, pri-miR-765 as well as a non-translated nucleotide sequence (miR-Ctrl) were expressed in adult mouse ventricular myocytes. The inhibitor-1 expression levels were decreased, accompanied by enhanced PP-1 activity in the miR-765 cardiomyocytes, and these reflected depressed contractile mechanics and Ca(2+) transients, compared with the miR-Ctrl group. The depressive effects were associated with decreases in the phosphorylation of phospholamban and SR Ca(2+) load. These miR-765 negative inotropic effects were abrogated in inhibitor-1-deficient cardiomyocytes, suggesting its apparent specificity for inhibitor-1.
CONCLUSIONS:
miR-765 levels are increased in human failing hearts. Such increases may contribute to depressed cardiac function through reduced inhibitor-1 expression and enhanced PP-1 activity, associated with reduced SR Ca(2+) load.
AuthorsWen-Feng Cai, Guan-Sheng Liu, Chi Keung Lam, Stela Florea, Jiang Qian, Wen Zhao, Tracy Pritchard, Kobra Haghighi, Djamel Lebeche, Long Jason Lu, Jingyuan Deng, Guo-Chang Fan, Roger J Hajjar, Evangelia G Kranias
JournalEuropean journal of heart failure (Eur J Heart Fail) Vol. 17 Issue 8 Pg. 782-93 (Aug 2015) ISSN: 1879-0844 [Electronic] England
PMID26177627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.
Chemical References
  • Intracellular Signaling Peptides and Proteins
  • MIRN765 microRNA, human
  • MicroRNAs
  • protein phosphatase inhibitor-1
  • Calcium
Topics
  • Animals
  • Blotting, Western
  • Calcium (metabolism)
  • Cells, Cultured
  • Heart Failure (physiopathology)
  • Humans
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Mice
  • MicroRNAs (physiology)
  • Myocardial Contraction (physiology)
  • Real-Time Polymerase Chain Reaction
  • Up-Regulation (physiology)

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