Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels.

Sebastián Dubó,Luis Sobrevia,Lissette Cabrera,David Gallegos,Marcelo González,Leandro Zúñiga

doi:10.3389/fphys.2016.00074

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.

Highlights

Specialty section: This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology
The SLC7A1 promoter belongs to the TATAless group, so binding sites for specificity protein 1 (Sp1) located near the transcription start site (TSS) would be responsible for both basal expression and regulation of gene expression to stimulation by growth factors (Sobrevia and González, 2009). These effects have been observed with physiologic concentrations of insulin (0.1–10 nM), so we propose that the expression of SLC7A1 and hCAT-1 activity would be under a tonic regulation by physiological levels of plasma insulin
Cardiovascular pathologies associated to insulin resistance are well documented, and we propose that the significant reduction of L-arginine transport mediated by lower expression and/or alteration of plasma membrane localization of the transporter could be a link between the impairment of insulin signaling and vascular disease

Summary

Introduction

Specialty section: This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology. 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. In 1990, in a study made in obese and lean subjects determined a correlation between insulin resistance (hyperglycaemia and hyperinsulinemia), and lack of vasodilatory effects of insulin in leg blood flow (LBF) These obese subjects showed a lower capacity for uptake D-glucose and changes in cardiac function, such as reduction in cardiac index [cardiac output (CO)/body surface area] and stroke volume (SV) without change in heart rate (HR) (Baron et al, 1990). We can propose a hypothesis for pathological mechanisms of cardiovascular disease in diabetes or insulin resistance

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