title: Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels.
abstract: Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K(+) (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or β-subunits (KChIP2 and MiRP) of K(+) channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology.
authors.affiliation: Department of Kinesiology, Faculty of Medicine, Universidad de Concepción Concepción, Chile.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Dubó
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Gallegos
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Department of Morphophysiology, Faculty of Medicine, Universidad Diego PortalesSantiago, Chile.
authors.forename: Lissette
authors.initials: L
authors.lastname: Cabrera
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, Pontificia Universidad Católica de ChileSantiago, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de SevillaSeville, Spain; Faculty of Medicine and Biomedical Sciences, University of Queensland Centre for Clinical Research (UQCCR), University of QueenslandHerston, QLD, Queensland, Australia.
authors.forename: Luis
authors.initials: L
authors.lastname: Sobrevia
authors.affiliation: Centro de Investigaciones Médicas, Escuela de Medicina, Universidad de Talca Talca, Chile.
authors.forename: Leandro
authors.initials: L
authors.lastname: Zúñiga
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Group of Research and Innovation in Vascular Health (GRIVAS-Health)Chillán, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: González
keywords: L-arginine; cardiac potassium channels; endothelium; heart failure; insulin; insulin resistance; nitric oxide; ventricular repolarization