Abstract 414: Putative Role of MicroRNA-143 in Modulating Natriuretic Peptide Signaling via Down-regulation of the Expression of Natriuretic Peptide Receptor 3

Cardiac natriuretic peptides (NPs) play important roles in the regulation of intravascular blood volume and vascular tone. Among other clearance mechanisms, bio-active circulating NPs are removed by the clearance receptor, Natriuretic Peptide Receptor 3 (NPR3). We hypothesized that the level of NPR3 could be modulated by microRNAs (miRNAs) resulting in changes in the bioactivity of NPs. We have previously reported a cluster of miRNAs potentially regulating NPR3 expression. To extend these findings, expression of the microRNAs concerned was examined in multiple platforms, including plasma from a clinical heart failure cohort, in the rat myocardial infarction model, and in a human cardiac derived cell line subjected to hypoxic challenge. Results: miR-143 was up-regulated in peripheral blood in heart failure patients compared with controls. The binding of miR-143 to the 3’UTR of NPR3 m RNA was verified by luciferase reporter assay. Antagomir-based silencing of miR-143 enhanced NPR3 expression in human derived cardiac cells. Elevation of miR-143 and down-regulation of NPR3 levels were observed in hypoxia treated cells and in the myocardium from the rat myocardial infarction model. Taken together, these findings suggest miR-143 may be involved in the down-regulation of NPR3 which in turn may provide more cardiac protective bioactivity from NPs in heart failure, myocardial hypoxic stress and in myocardial infarction. In summary, NPR3 is negatively regulated by miR-143, pointing to the therapeutic potential of miR-143 to beneficially enhance NP responses.