Inhibition of aldose-reductase-2 by a benzofuroxane derivative bf-5m increases the expression of kcne1, kcnq1 in high glucose cultured H9c2 cardiac cells and sudden cardiac death

// Maria Consiglia Trotta 1, * , Monica Salerno 2, * , Anna Lisa Brigida 1 , Vincenzo Monda 3 , Antonietta Messina 3 , Carmela Fiore 2 , Roberto Avola 4 , Renato Bernardini 4 , Francesco Sessa 2 , Gabriella Marsala 5 , Guido N. Zanghi 6 , Giovanni Messina 2 , Michele D’Amico 1 and Clara Di Filippo 1 1 Department of Experimental Medicine, Division of Pharmacology, University of Campania L. Vanvitelli, Naples, Italy 2 Department of Clinical and Experimental Medicine University of Foggia, Foggia, Italy 3 Department of Experimental Medicine, Section of Human Physiology and Dietetic and Sport Medicine, University of Campania L. Vanvitelli, Naples, Italy 4 Department of Biomedical and Biotecnological Sciences, University of Catania, Catania, Italy 5 Struttura Complessa di Farmacia, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Foggia, Foggia, Italy 6 Department of Surgery, Policlinico Vittorio Emanuele University Hospital, University of Catania, Catania, Sicily, Italy * These authors contributed equally to this work Correspondence to: Giovanni Messina, email: giovanni.messina@unifg.it Keywords: long qt interval; hyperglycemia; sudden cardiac death; BF-5m; KCNQ1 and KCNE1 ion channels; Gerotarget Received: November 27, 2017 Accepted: December 08, 2017 Epub: December 14, 2017 Published: April 03, 2018 ABSTRACT Long QT syndrome (LQTS) is characterized by prolonged QT interval, leading to sudden cardiac death. Hyperglycemia is an important risk factor for LQTS, inhibiting the cardiac rapid component delayed rectifier K+ current (Iks), responsible for QT interval. We previously showed that the new ALR2 inhibitor BF-5m supplies cardioprotection from QT prolongation induced by high glucose concentration in the medium, reducing QT interval prolongation and preserving morphology. Here we investigated the effects of BF-5m on cell cytotoxicity and viability in H9c2 cells, and on cellular potassium ion channels expression. H9c2 cells were grown in medium with high glucose and high glucose plus the BF-5m by assessing the cytotoxic effects and the cell survival rate. In addition, KCNE1 and KCNQ1 expression in plasma and mitochondrial membranes were monitored. Also, the expression levels of miR-1 proved to suppress KCNQ1 and KCNE1, were analyzed. BF-5m treatment reduced the cytotoxic effects of high glucose on H9c2 cells by increasing cell survival rate and improving H9c2 morphology. Plasmatic KCNE1 and KCNQ1 expression levels were restored by BF-5m in H9c2 exposed to high glucose, down-regulating miR-1. These results suggest that BF-5m exerts cardioprotection from high glucose in rat heart ventricle H9c2 cells exposed to high glucose.