Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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, Monica Salerno, Anna Lisa Brigida, Vincenzo Monda, Antonietta Messina, Carmela Fiore, Roberto Avola, Renato Bernardini, Francesco Sessa, Gabriella Marsala, Guido N. Zanghì, Giovanni Messina _, Michele D’Amico and Clara Di Filippo

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Oncotarget. 2018; 9:17257-17269. https://doi.org/10.18632/oncotarget.23270

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Abstract

Maria Consiglia Trotta1,*, Monica Salerno2,*, Anna Lisa Brigida1, Vincenzo Monda3, Antonietta Messina3, Carmela Fiore2, Roberto Avola4, Renato Bernardini4, Francesco Sessa2, Gabriella Marsala5, Guido N. Zanghì6, Giovanni Messina2, Michele D’Amico1 and Clara Di Filippo1

1Department of Experimental Medicine, Division of Pharmacology, University of Campania L. Vanvitelli, Naples, Italy

2Department of Clinical and Experimental Medicine University of Foggia, Foggia, Italy

3Department of Experimental Medicine, Section of Human Physiology and Dietetic and Sport Medicine, University of Campania L. Vanvitelli, Naples, Italy

4Department of Biomedical and Biotecnological Sciences, University of Catania, Catania, Italy

5Struttura Complessa di Farmacia, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Foggia, Foggia, Italy

6Department 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: [email protected]

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.


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