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.
Highlights
Diabetes mellitus (DM) is a chronic and major disease affecting a large population in US and across the world
Structural remodeling of diabetic heart Age-matched (13–14 week) db/db mice and Wild type (Wt) mice from Jackson Laboratory were used in the study
There is no significant difference in the RV wall thickness, we observed a significant increase in LV wall thickness, and a decrease in septal wall thickness in db/db hearts compared with wild type (Fig.1f–h)
Summary
Diabetes mellitus (DM) is a chronic and major disease affecting a large population in US and across the world. Diabetic cardiomyopathy (DCM) accounts for 70% deaths among diabetic patients. DCM leads to the inability of the heart to circulate blood efficiently and the disease progression is mostly asymptomatic until late stages. Current understanding in this area indicates that diabetics have increased incidences of sudden cardiac death due to myocardial ischemia (MI), when compared to non-diabetics [1,2]. The heart is a highly metabolic organ which functions as a synchronized electrical unit for pumping of oxygenated blood to the body. The electrical activity is compromised and predisposes the heart to maladaptation and metabolic disturbances
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