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.

Pro-angiogenic Role of Insulin: From Physiology to Pathology

“…For instance, insulin induces vasorelaxation, enhances endothelial uptake of amino acids (such as L-arginine) and increases survival and migration of endothelial cells (Dubó et al, 2016; Sobrevia et al, 2016). These actions, combined with the capacity of insulin to enhance expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), as well as increase pericytes survival and reduce anti-angiogenic protein expression, have established the role of insulin in physiological and pathological angiogenesis (He et al, 2006).…”

Whole‐exome sequencing reveals microsatellite DNA markers for response to dofetilide initiation in patients with persistent atrial fibrillation: A pilot study

“…It was shown using a canine model that GLUT4 is differentially expressed between chambers of the heart with decreased expression in the right atrium in subjects with heart failure. Moreover, it has been demonstrated that impaired insulin signaling in cardiac myocytes can result in prolonged ventricular action potential duration and subsequently prolonged QT intervals. It is possible that the failure of dofetilide‐ineligible patients to mobilize sufficient GLUT4 to the plasma membrane via MYH6 and MYH13 can result in prolonged QT intervals.…”

Резистентність До Інсуліну, Її Зв’язок З діастолічною Дисфункцією Лівого Шлуночка Та еластичністю Аорти У хворих З артеріальною Гіпертензією

“…У роботах вітчизняних і зарубіжних авторів вка-зується, що за наявності АГ виникає стан ІР, що су-проводжується порушенням ліпідного обміну, ві-рогідною кореляцією між рівнем інсуліну та масою міокарда ЛШ [1,4]. У нашій роботі встановлено взаємозв'язок між ступенем ІР, розрахованим у мо-делі HOMA-2, та ймовірністю розвитку ДД ЛШ і розвитком макроангіопатій у вигляді зниження еластичності аорти у хворих за поєднаного перебі-гу АГ та ЦД типу 2, а також за наявності ізольова-ної АГ.…”