Connexin 43 (Cx43) plays a vital role in maintaining myocardial function through gap junctions (GJs) and hemichannels (HCs), facilitating crucial intercellular communication and ion exchange. Its regulation is precisely controlled by various signaling pathways that influence its phosphorylation status, trafficking, and degradation, thereby modulating myocardial function under physiological and pathological conditions. Under pathological conditions such as ischemic injury, cardiomyopathies, or heart failure, Cx43 undergoes dephosphorylation and is mislocalized from GJs at intercalated discs to the lateral membrane. This disruption in intercellular connectivity impairs electrical conduction and increases susceptibility to arrhythmias, with the loss of functional Cx43-mediated GJs further exacerbating myocardial dysfunction and contributing to disease progression. Given the critical role of Cx43 in cardiac pathology, therapeutic strategies targeting Cx43, particularly peptidomimetics, have emerged as promising cardioprotective approaches. These small synthetic peptides selectively modulate Cx43 HC activity, preventing excessive cellular stress and preserving intercellular communication. Recent advancements, including TAT-conjugated peptides and Hdc-modified analogues, have enhanced the efficacy of peptidomimetics by improving cellular uptake and therapeutic effectiveness. This review highlights the role of Cx43 and Cx43-derived peptidomimetics in cardiovascular diseases, noting their promising potential for broader clinical applications due to Cx43 dysregulation being implicated in various pathologies. Keywords Connexin 43 " Gap Junctions " Myocardial dysfunction " Peptidomimetics.

Institute of Pharmacology and Clinical Pharmacology Faculty of Medicine Comenius University Bratislava Bratislava Slovakia

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