Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

Abstract

The heart is a complex organ composed of multiple cell types, including cardiomyocytes and different non-myocyte populations, all working closely together to determine the hearts properties and maintain normal cardiac function. Connexins are abundantly expressed proteins that form plasma membrane hemichannels and gap junctions between cells. Gap junctions are intracellular channels that allow for communication between cells, and in the heart they play a crucial role in cardiac conduction by coupling adjacent cardiomyocytes. Connexins are expressed in both cardiomyocytes and non-myocytes, including cardiac fibroblasts, endothelial cells, and macrophages. Non-myocytes are the largest population of cells in the heart, and therefore it is important to consider what roles connexins, hemichannels, and gap junctions play in these cell types. The aim of this review is to provide insight into connexin-based signalling in non-myocytes during health and disease, and highlight how targeting these proteins could lead to the development of novel therapies. We conclude that connexins in non-myocytes contribute to arrhythmias and adverse ventricular remodelling following myocardial infarction, and are associated with the initiation and development of atherosclerosis. Therefore, therapeutic interventions targeting these connexins represent an exciting new research avenue with great potential.

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

“…Interestingly, connexin 43 appeared to be reduced and disrupted at the intercalated disk in DSS rats, an effect partially reversed after treatment. Taken together, these findings suggest that a functional NO-sGC-cGMP pathway preserves the intercalated disk, the site of mechanical and electrical conduction between cardiomyocytes and perhaps also fibroblasts (Menges et al, 2019) and endothelial cells (Yuan et al, 2015;Johnson and Camelliti, 2018). Connexin 43 expressed in endothelial cells modulates monocyte-endothelial adhesion by regulating cell adhesion proteins, an interaction that is decreased upon reduced connexin 43 (Yuan et al, 2015).…”

Telmisartan cardioprotects from the ischaemic/hypoxic damage through a miR‐1‐dependent pathway

“…What still required deeper evaluation were the cell types which telmisartan‐activated and the sequence of events. It is opinion that, although non‐cardiomyocyte cells of the heart express Cnx43 gap junctions and are able to influence cardiac electrophysiology, KCNQ1 channels are a predominant feature of cardiac myocytes . Similarly, it is opinion that there should be a coordinated and sequential action by telmisartan on the factors monitored, probably through miR‐1 first and then on the other two.…”

“…It is opinion that, although non-cardiomyocyte cells of the heart express Cnx43 gap junctions and are able to influence cardiac electrophysiology, KCNQ1 channels are a predominant feature of cardiac myocytes. [48][49][50] Similarly, it is opinion that there should be a coordinated and sequential action by telmisartan on the factors monitored, probably through miR-1 first and then on the other two. Therefore, in order to investigate a possible Cnx43/KCNQ1 modulation afforded by telmisartan through miR-1 regulation, we translated the research on cultured hypoxic/reoxygenated embryonic rat H9c2 cardiomyocytes exposed to the hypoxia-mimetic chemical cobalt chloride (CoCl2), and treated with telmisartan.…”

Cardiomyocyte—Endothelial Cell Interactions in Cardiac Remodeling and Regeneration

“…In addition to paracrine mediators, also direct physical cell-cell contacts may play a role in EC-CM communication. Connexins are important in cell-cell communication and Cx43, Cx40, and Cx37 are expressed in both ECs and CMs [reviewed in ( 60 )]. They form gap junctions between adjacent CMs enabling efficient electrical conduction.…”