This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply.

Connexin43 (Cx43) is commonly associated with direct cell-cell communication through gap junctions (GJs). However, recent groundbreaking studies have challenged this dogma, implicating Cx43 in other biological processes, such as transcription, metabolism, autophagy, and ion channel trafficking. How Cx43 participates in these processes remains largely unknown, although its high turnover rate, capacity to bind to myriad proteins, and the discovery of truncated isoforms of Cx43, ascribe to this protein unanticipated roles in chief processes that require fine-tuned regulation. Accordingly, Cx43 can be regarded as a central integrative hub to which diverse cues converge to be processed in a concerted manner. In this review, we examine the noncanonical roles of Cx43 and discuss the implications of these functions in human diseases and future therapeutic strategies. A Second Life for an Old-Fashioned Protein: The Role of Cx43 Beyond Gap Junction Communication Channel-forming connexin proteins are canonically associated with gap junction (GJ)-mediated communication between adjacent cells, ensuring both metabolic and electrical coupling, fundamental for tissue and organ homeostasis (Box 1). As a result, GJ-mediated intercellular communication (GJIC) has been the main focus in the connexin field over the past 30 years. However, emerging evidence has ascribed unanticipated biological roles to connexins that go beyond direct intercellular communication, pointing towards broader functions of these membrane proteins. For example, unbiased proteomic approaches of Connexin43 (Cx43), have revealed a long list of binding proteins related to various biological processes and mechanisms. Moreover, the presence of Cx43 in intracellular compartments, including the nucleus and mitochondria, has been reported. Several studies have unveiled these noncanonical functions in detail, associating Cx43 with features such as gene transcription, development, mitochondrial homeostasis, autophagy (see Glossary) regulation, intracellular trafficking, and long-distance communication mediated by extracellular vesicles (EVs). Here, we present an integrated overview of the recent literature that has revealed unforeseen functions for connexins, with a particular focus on Cx43. In fact, Cx43 is the most ubiquitously distributed family member, expressed in multiple cell types across almost all tissues and organs. This has favored its study as a model for other connexins. Most of the differential features attributed to each connexin family member have been related to the size and variability of their intracellular loop and C terminus [1]. In agreement, many of the noncanonical roles of Cx43 have been ascribed to its cytosolic C-terminal tail constituting a preferential platform to accommodate diverse protein-protein interactions. Given its unusual versatility and short half-life, it is conceivable that the evolutionary selection of Cx43 as the predominant connexin isoform in mammals makes it a preferential protein to exhibit biological functions beyond GJIC...

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.