Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

Abstract

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.

Sevoflurane Improves Ventricular Conduction by Exosomes Derived from Rat Cardiac Fibroblasts After Hypothermic Global Ischemia-Reperfusion Injury

“…9,21 A previous study showed that the expression of miR-1 increased and was subsequently regulated to lower the expression of Cx43 under oxidative stress. 20 Our investigation demonstrated that while CFs-exo boosted the expression of Cx43 in ventricular tissues, however, Sev-CFs-Exo significantly enhanced it. Meanwhile, both of them could reduce the distribution of Cx43 to the lateral membrane.…”

“…19 The principal connexin in the ventricle is connexin 43 (Cx43), and its expression is regulated by microRNA-1. 20 Abnormal expression and location of Cx43 in ischemia-reperfusion myocardium is closely related to RA, and up-regulation of Cx43 expression can reduce the risk of RA. 21 Sevoflurane is one of the most commonly utilized halogenated inhalational anesthetics in CPB surgery because of its low blood-gas partition coefficient, high anesthetic efficiency and no discernible influence on heart rates (HR).…”

Electrical Stimulation Increases the Secretion of Cardioprotective Extracellular Vesicles from Cardiac Mesenchymal Stem Cells

“…Meraviglia V et al [ 69 ] reported that ELSM significantly reduced the expression of connexin43 (Cx43) by increasing the acetylation of Cx43 on HL-1 cardiomyocytes at 0.5 Hz for 24 h, suggesting that ELSM may reduce the expression of Cx43 by affecting the protein level of Cx43 and reducing cardiomyocyte-to-cardiomyocyte communication. Another report suggested that Cx43 expression was highly sensitive to ELSM in a frequency-dependent manner that high stimulation frequency leads to a substantial reduction in global Cx43 expression in murine-induced pluripotent stem cell-derived cardiomyocytes by promoting the expression of microRNA-1, which targets Cx43 [ 70 ]. It would be interesting to see whether ELSM inhibits Cx43-dependent cell-cell communications and enhances EV-mediated intracellular communications.…”

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

“…Cx43 is found in gap junctions and is critical for both metabolic and electrical coupling of cardiomyocytes as well as other cells [ 52 ]. In fact, a loss of function in the gap junctions has been associated with HFrEF as well as lethal arrhythmias [ 18 , 53 ]. BAG3 has also been shown to regulate the physiologic maintenance and pathologic degradation of Cx43.…”