Acute Alcohol Treatment and Cardiac Dysfunction in Obese Diabetic Mice: Role of PDE5 and MicroRNA‐21

Abstract

ObjectiveExcessive intake of alcohol under diabetic condition leads to increased stress and causes both transient and lasting structural changes including fibrosis in heart. We tested the hypothesis whether phosphodiesterase5 (PDE5) inhibitor, sildenafil prevents alcohol‐induced cardiac dysfunction in Type 2 Diabetic (T2D) db/db mice and the role of microRNA‐21(miR‐21) in fibrosis through regulation of ERK1/2‐MAP kinase signaling and sprouty‐1(Spry‐1).Methods and ResultsAdult male db/db mice were randomized to receive: saline as control (0.2 ml; i.p, n =9) or ethanol (1.5 g/ BID; i.p, n=5) or ethanol with sildenafil (0.7mg/kg/day; i.p, n=5) for 3 days. Echocardiography showed a decline in Ejection Fraction (EF) in mice treated with ethanol as compared to their baseline (P < 0.05). Treatment with sildenafil in combination with ethanol showed normal EFimage). Real time PCR using TaqMan microRNA probe showed 1.5 fold increase in miR‐21 level in the heart after alcohol treatmentimage). Protein analysis showed down regulation of spry‐1, a target of miR‐21 and upregulation of ERK‐1/2 phosphorylation. Sildenafil treatment prevented the upregulation of miR‐21 and hence increased the level of spry‐1 and a concomitant decrease in ERK‐1/2 phosphorylation.ConclusionThe induction of miR‐21 in ethanol treated db/db mice with a subsequent decrease in spry‐1 and an increase in Phosphorylation of ERK‐1/2 suggest a role of this signaling cascade in fibrosis and cardiac dysfunction. Therapeutic intervention using sildenafil prevented LV dysfunction caused by alcohol intake and trigger of fibrosis signaling pathway.This study was supported in part by grants from National Institutes of Health (HL51045, HL79424, HL118808 to RCK).