Abstract 318: Heterogeneous Remodeling in Diabetic Hearts Leads to Sudden Cardiac Death
Diabetes increases propensity to sudden cardiac death. Although ion channels were implicated, the precise mechanisms leading to arrhythmias remain unclear. We hypothesized that the diabetic heart undergoes heterogeneous remodeling leading to arrhythmogenic substrate and sudden cardiac death. For this, we investigated the expression of cardiac specific microRNAs, key transcriptional factors and their target gene in right (RV) and left ventricle (LV). TaqMan and SYBR green qRT-PCR was used to estimated the transcriptional data and Western blots/ELISA for protein profiles. Our data clearly suggests that miR-1-1a (1.6±0.021; p≤0.00067) and miR-301 (1.36±0.02; p≤0.0201) were up-regulated in epicardium of left ventricle (LV-epi), whereas miR-1-1a (2.9±0.59; p≤0.027), miR-133a (3.7±0.19; p ≤ 0.041) and miR-301 (3.6±0.26; p-value ≤ 0.037) were up-regulated in RV of diabetic (db/db) mice (n=3) hearts compared with wild type (n=3). Out of 30 genes tested we confirmed down-regulation of 14 genes (with p≤0.05) including transcriptional factors NFkB2, GATA6, Irx5, Ezh-2, Six-1, CtBP, SiRT1; ion channels Kv4.2, Scn1b and Scn5a and its protein chaperon Kchip-2, whereas Mef2c was up-regulated significantly in LV-epi in diabetic mice. Similarly, 11 genes including Kv4.2, Mef2c, GATA4, GATA6, Pitx2c, Scn1b, Kchip-2, SiRT1, Nampt and MMP-9 were down-regulated (p≤0.05), whereas 9 genes such as Irx5, Kv2.1, Kv4.3, NFkB1, NFkB2, MHC7, CtBP, NNt, and G6PD were up-regulated significantly in RV of diabetic mice. The Ingenuity Pathway Analysis of the differentially expressed genes in heart revealed hypertrophy, arrhythmias, proliferation, and failure as top toxicology networks in LV-epi, whereas cardiac hypertrophy, hepatic stellate cell activation, oxidative stress, PPAR mediated gene activation, fibrosis and necrosis are among top toxicology networks in RV. The role of miR’s along with transcriptional factors down-regulating Kv4.2 in diabetic LV may be consistent with the idea that repolarization reserve is decreased in diabetic hearts. Moreover, regional differences in potassium current may play vital role in regulating function. These data suggest that the ion channel remodeling in left and right ventricles are modulated via different mechanisms.
- © 2012 by American Heart Association, Inc.