Abstract 13120: Identification of Novel Circulating microRNAs in Ischemic Cardiomyopathy Utilizing Whole Blood microRNA Profiling
microRNAs (miRs) have emerged as important regulators of gene expression within cardiac development and disease. Additionally, miRs are released into the circulation wherein their dysregulation can provide insight into disease mechanisms occurring in the tissue of origin. We hypothesized that whole blood miR profiling would identify uniquely dysregulated miRs in the setting of ischemic cardiomyopathy (ICM), thereby providing insight into novel pathways and therapeutic targets in this disease state. To this end we performed comprehensive profiling of 1040 miRs on the whole blood of ICM mice (LAD ligation model; n=5) and control, SHAM mice (n=4). Fifty miRs were found to be significantly dysregulated. From a molecular standpoint, 38 miRs were involved in cellular growth/proliferation, 18 miRs were involved in cell cycle regulation, and 24 miRs were involved in modulating cell death/survival. Expression profiles of the top 10 dysregulated miRs were subsequently assessed in a validation cohort of mice (3 ICM, 3 SHAM), as well as in human patients with decompensated ischemic cardiomyopathy (n=10) compared to healthy controls (n=3). Two miRs were found to have consistent dysregulation across species. miR-361 was up-regulated 50-fold (p<0.01), while miR-1187 was downregulated 2-fold (p<0.01) in ICM patients vs healthy, controls. Given the marked upregulation of miR-361, TargetScan was utilized to identify downstream targets of miR-361. Core analysis of these downstream targets utilizing Ingenuity Pathway Analysis suggested miR-361 regulates cellular growth and cell death. qRT-PCR data revealed the expression of several of these downstream targets, including Bcl2l2, Casp7, and Ep300 , were reduced in ICM patients. In conclusion, a unique whole blood miR signature was identified in mice and humans with ischemic cardiomyopathy and enabled the discovery of two circulating miRs (miR-361 and miR-1187), not previously associated with this disease entity. Dysregulation of circulating miR-361 and miR-1187 expression in the setting of ischemic cardiomyopathy across two mammalian species suggests these miRs may serve important roles in the pathophysiology of this disease.
- © 2013 by American Heart Association, Inc.