Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

Abstract

Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo animal models of cardiac ischemia/reperfusion (I/R) injury are robustly used in research. Connexin43 (Cx43), the predominant gap junction channel-forming protein in cardiomyocytes, has emerged as a cardioprotective target. Cx43 posttranslational modifications as well as cellular distribution are altered during cardiac reperfusion injury, inducing phosphorylation states and localization detrimental to maintaining intercellular communication and cardiac conduction. Pre- (before ischemia) and post- (after ischemia but before reperfusion) conditioning can abrogate this injury process, preserving Cx43 and reducing cell death. Pre-/post-conditioning has been shown to largely rely on the presence of Cx43, including mitochondrial Cx43, which is implicated to play a major role in pre-conditioning. Posttranslational modifications of Cx43 after injury alter the protein interactome, inducing negative protein cascades and altering protein trafficking, which then causes further damage post-I/R injury. Recently, several peptides based on the Cx43 sequence have been found to successfully diminish cardiac injury in pre-clinical studies.

Cardiac Connexin-43 Hemichannels and Pannexin1 Channels: Provocative Antiarrhythmic Targets

“…Some HCs in peri-junctional membranes (peri-nexus) do not undergo docking, and exert specific non-canonical functions beyond GJCs [ 25 , 34 , 35 ]. However, their mutual proximity implies integrated HCs and GJCs interaction and cooperation ( Figure 1 e,f).…”

“…These undergo degradation by proteasomes and lysosomes [ 27 , 29 , 30 , 31 , 46 ]. However, the considerably rapid HCs/GJCs turnover is most important because it illustrates the dynamic nature of intercellular communication and Cx43 mediated signaling [ 25 , 27 , 35 , 37 , 48 ]. In contrast to the Cx43 protein, the Panx1 channels are composed of long-lived pannexin proteins which suggests a slower life cycle where internalized pannexins are degraded by lysosomes [ 38 ].…”

“…This network coordinates myocardial contraction. It is also the most important in heart adaptation, and especially for the response to stressful or pathophysiological conditions by propagating both cell survival and apoptosis signals [ 20 , 22 , 25 , 37 , 38 , 46 , 51 , 54 ]. It is a fundamental and permanent task to control this network when trying to prevent or treat heart and life-threatening arrhythmias.…”

“…Very attractive are, therefore, recent investigations highlighting an important role of paracrine intercellular communication mediated by Cx hemichannels (HCs) as well as by pannexin channels in various tissues, including the cardiovascular system [ 20 , 21 , 22 , 23 , 24 , 25 ]. These channels are active in stressful conditions, and essential for paracrine signaling through the release of ions and molecules to the extracellular environment, and/or for their uptake.…”

“…These channels are active in stressful conditions, and essential for paracrine signaling through the release of ions and molecules to the extracellular environment, and/or for their uptake. The opening of HCs and/or structurally similar pannexin1 (Panx1) channel profoundly affects intracellular ionic homeostasis, redox status, and facilitates pro-inflammatory and pro-fibrotic processes via purinergic signaling [ 22 , 25 , 26 ]. These conditions may promote myocardial arrhythmogenesis due to the impairment of the GJCs and selective ion channel function.…”