MicroRNA-301a mediated regulation of Kv4.2 in diabetes: identification of key modulators

• Published in: PloS one Vol. 8; no. 4; p. e60545
• Main Authors: Panguluri, Siva K, Tur, Jared, Chapalamadugu, Kalyan C, Katnik, Chris, Cuevas, Javier, Tipparaju, Srinivas M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-04-2013; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; Animals; Base Sequence; Binding Sites; Biology; Cardiac arrhythmia; Cardiology; Cardiomyocytes; Cardiomyopathy; Cardiovascular diseases; Cardiovascular system; Cell Line; Complications; Coronary artery disease; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Diabetic Cardiomyopathies - metabolism; Gene expression; Genetic aspects; Health risks; Heart diseases; Heart failure; Heart Ventricles - metabolism; In vivo methods and tests; Ion channels; Ischemia; Medicine; Membrane Potentials; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Modulators; Molecular Sequence Data; Myocardium - pathology; NF-κB protein; Patch-Clamp Techniques; Pharmaceutical sciences; Pharmacy; Physiology; Potassium; Potassium channels (voltage-gated); Rats; Ribonucleic acid; RNA; RNA Interference; Rodents; Shal Potassium Channels - genetics; Shal Potassium Channels - metabolism; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Transcriptome; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Ventricular Remodeling; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060545

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.