Abstract 19865: Exploring miRNA-mRNA Regulatory Network in Cardiac Pathology of Na+/H+ Exchanger Isoform 1 Transgenic Mouse Hearts
Numerous studies have demonstrated that elevated activity of Na+/H+ exchanger isoform 1 (NHE1) in myocardial diseases is detrimental. To better understand the involvement of NHE1, cardiac-specific NHE1 transgenic mice with overexpression of a constitutively active NHE1 allele were studied. We have previously shown that NHE1 transgenic mice develop cardiac hypertrophy, interstitial fibrosis as well as depressed cardiac function (Xue 2010). The purpose of the current study was to identify microRNAs (miRNAs) and their mRNA targets involved in NHE1-mediated cardiac injury. An un-biased high throughput sequencing study was performed on both miRNAs and mRNAs. RNA sequencing showed that differentially-expressed genes were enriched in hypertrophic/dilated cardiomyopathy (HCM/DCM) pathways by Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation in NHE1 transgenic hearts. These genes were classified as contraction defects (e.g. Myl2, Myh6, Mybpc3 and Actb), impaired intracellular Ca2+ homeostasis (e.g. SERCA2a, Ryr2, Rcan1 and CaMKII delta) and signaling molecules that cause HCM and DCM (e.g. Itga/b, IGF-1, Tgfb2/3 and Prkaa1/2). miRNA sequencing revealed that fifteen miRNAs were differentially-expressed (2 fold, P<0.05) in NHE1 transgenic mice as compared to wild type controls. Six of them have been shown to be related to cardiac pathological function, including miR-1-3p, miR-208a-3p, miR-199a-5p, miR-21-5p, miR-146a-5p and miR-30c-5p. The integrative analysis of miRNAs and RNA sequencing data identified several crucial miRNAs including miR-30c-5p, miR-199a-5p, miR-21-5p and miR-34a-5p as well as ten of their mRNA targets that may work via NFAT cardiac hypertrophy pathway and lead to cardiac pathology. Our study comprehensively characterizes the expression patterns of miRNAs and mRNAs, establishes functional miRNA-mRNA pairs, elucidates the potential signaling pathways and provides novel insights on the mechanisms underlying NHE1-mediated cardiac injury.
Author Disclosures: J. Xue: None. D. Zhou: None. I. Hartley: None. O. Poulsen: None. G.G. Haddad: None.
- © 2016 by American Heart Association, Inc.