MicroRNA-301a Mediated Regulation of Kv4.2 in Diabetes: Identification of Key Modulators

Abstract

Diabetes is a metabolic disorder that ultimately results in major pathophysiological complications in the cardiovascular system. Diabetics are predisposed to higher incidences of sudden cardiac deaths (SCD). Several studies have associated diabetes as a major underlying risk for heart diseases and its complications. The diabetic heart undergoes remodeling to cope up with the underlying changes, however ultimately fails. In the present study we investigated the changes associated with a key ion channel and transcriptional factors in a diabetic heart model. In the mouse db/db model, we identified key transcriptional regulators and mediators that play important roles in the regulation of ion channel expression. Voltage-gated potassium channel (Kv4.2) is modulated in diabetes and is down regulated. We hypothesized that Kv4.2 expression is altered by potassium channel interacting protein-2 (KChIP2) which is regulated upstream by NFkB and miR-301a. We utilized qRT-PCR analysis and identified the genes that are affected in diabetes in a regional specific manner in the heart. At protein level we identified and validated differential expression of Kv4.2 and KChIP2 along with NFkB in both ventricles of diabetic hearts. In addition, we identified up-regulation of miR-301a in diabetic ventricles. We utilized loss and gain of function approaches to identify and validate the role of miR-301a in regulating Kv4.2. Based on in vivo and in vitro studies we conclude that miR-301a may be a central regulator for the expression of Kv4.2 in diabetes. This miR-301 mediated regulation of Kv4.2 is independent of NFkB and Irx5 and modulates Kv4.2 by direct binding on Kv4.2 3′untranslated region (3′-UTR). Therefore targeting miR-301a may offer new potential for developing therapeutic approaches.

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…Alterations of the spatial heterogeneity of ion channel expression and AP duration have been previously reported in rodent models of diabetes,45, 56, 57 which are consistent, at least in part, with our observation of a preferential prolongation of duration of MAPs in the epicardial/apical region of STZ hearts. The altered regional properties of cardiac tissue may have affected locally the refractoriness of the myocardium, negatively interfering with electrical conduction and pattern of impulse propagation.…”

“…Reductions of the K + channel subunit, Kv4.2, interacting protein KChIP2, and Ca 2+ channel α‐1C subunit have been proposed as molecular substrates for the decreased Kv currents and I CaL in myocytes from rodent models of diabetes 43, 45, 46, 47, 57, 59. Our electrophysiological data support the possibility that similar alterations occur in the STZ‐hyperglycemic mouse model employed here.…”

Role of microRNAs in the pathogenesis of diabetic cardiomyopathy

“…Furthermore, analysis of miR expression levels in the hearts of various rat and mouse diabetic models also indicated the abnormal expression of miRNA. Further studies demonstrated that miRs contribute to numerous important pathophysiological processes of DCM, including cardiomyocyte hypertrophy, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial dysfunction, myocardial electrical remodeling and epigenetic modification (27)(28)(29)(30)(31)(32). The present review discusses the possible role of miRs in the pathogenesis of DCM regarding the above-mentioned processes.…”

“…miRs are also involved in the pathogenesis of DCM through participating in various pathophysiological processes, such as myocardial electrical remodeling and epigenetic modification (27,31). A significant increase in the level of miR-301 expression and reduction of the voltage gated potassium channel, Kv4.2 expression level were observed in the diabetic (db/db mice) ventricles and miR-301 was validated to modulate Kv4.2 by direct binding on its 3'-UTR (31).…”

Overexpression of miR‑130a‑3p/301a‑3p attenuates high glucose‑induced MPC5 podocyte dysfunction through suppression of TNF‑α signaling

“…Recently, several studies have highlighted the significance of miRs in maintaining glucose metabolism-associated cell dysfunction (11)(12)(13). For example, miR-130a-3p has been shown to mediate insulin sensitivity (10), and miR-24-3p, miR-146a-5p, miR-194-5p, miR-197-3p, miR-301a-3p and miR-375 are correlated with residual beta cell function in children with new-onset type 1 diabetes mellitus (T1DM) (12).…”