Abstract 3864: MicroRNA-152 Represses SERCA2a and Contributes to the Impairment of Cardiomyocyte Contractile Function
Abnormalities in expression of small non-coding RNA molecules known as microRNAs (miRNAs) appear to be associated with cardiac dysfunction in humans. We have performed comprehensive microarray profiling of miRNAs in a rat model of heart failure as well as in left ventricular specimens from human failing hearts. We have observed a robust up-regulation of miR-152 in failing samples in comparison to non-failing hearts. Using computational target prediction algorithms we have identified ATP2A2 as a specific miR-152 target. ATP2A2 encodes for the Sarco(endo)plasmic reticulum Ca2+-ATPase type-2 isoform (SERCA2a) pump and is an important regulator of intracellular Ca2+ signaling in the heart. In gain-of-function experiments using adenoviral-mediated gene delivery we have shown that over-expression of miR-152 resulted in diminished SERCA2a protein and mRNA levels in rat ventricular cardiomyocytes in vitro. The direct targeting of Serca2a by miR-152 was confirmed using luciferase reporter gene assays. Functional assessments of contractility and intracellular calcium ([Ca2+]i) transients were also measured in isolated myocytes. Contractile behavior of myocytes over-expressing miR-152 displayed reductions in myocyte fractional shortening and velocity of shortening. In addition, intracellular calcium transient were characterized with elevated diastolic calcium levels, a decreased systolic calcium and prolonged relaxation phase. These alterations are characteristics of the failing myocyte. Our data demonstrates that up-regulation of miR-152 correlates with a decrease in the relative expression of SERCA2a suggesting that it may contribute to the cardiac myocyte dysfunction, which characterizes the progression of heart failure. Thus, miR-152 may represent a new therapeutic target for heart diseases.