WCN26-3678 Endothelial DNA damage orchestrates cardio-kidney-metabolic dysfunction through endothelin-1 signaling

Introduction: Extensive scar formation following myocardial infarction (MI) has a negative impact on cardiac function, thus promoting heart failure development.Therefore, therapies limiting scar formation post-MI are highly needed.Methods: Mice subjected to chronic ligation of the left anterior descending coronary artery were treated with VIF applied subcutaneously for two weeks post-MI and then analyzed at different time points in vivo and ex vivo.Results: VIF treatment resulted in a lower mortality rate (20%) compared to the saline-treated group (60%).In addition, VIF treatment improved left ventricular ejection fraction and reduced myocardial scar size compared to control mice.Moreover, VIF-treatment influenced the extracellular matrix composition by increasing collagen-5 content in the myocardial scar tissue andupregulating collagen-5 gene expression.Furthermore, VIF treatment led to upregulation of conditioning genes with protective effects against hypoxia-induced injury, such as HIF-1 and HMOX-1, as well as anti-apoptotic gene BCL-2 in AC16 cardiomyocytes, compared to control cells.Finally, patients with ACS exhibited increased VIF plasma levels compared to healthy subjects, raising the hypothesis of a compensatory effect of VIP to prevent endorgan damage.Conclusion: Following myocardial infarction, VIF treatment provides cardioprotection through two key mechanisms: (i) VIF activates conditioning genes such as HIF-1 and HMOX-1, helping cardiomyocytes survive hypoxic injury as an adaptive response, and (ii) VIF modulates extracellular matrix composition which reduces scar size and therefore improves the left ventricular ejection fraction.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.