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Impaired sarcoplasmic reticulum (SR) Ca²⁺ 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.

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 …