Caractérisation de substances naturelles actives sur la fonction cardio-vasculaire à partir de venin de la vipère libanaise, Montivipera bornmuelleri et d’une chimiothèque d’alcaloïdes de plantes : Identification d’un nouveau peptide vasorelaxant iss

Hypertension, the leading cause of cardiovascular diseases and premature death, remains inadequately controlled, emphasizing the need for new treatments. Viperid snakebites cause hypotension, as molecules in their venoms induce arterial vasorelaxation, reducing blood pressure. Vipers of the Montivipera genus, endemic to the Near and Middle East, have poorly studied venoms, and their vasorelaxant effects have not been explored. Additionally, proteomic analyses of Montivipera venoms have been inconsistent. Our study aimed to pharmacologically characterize the vasorelaxant effects of Montivipera venoms using wire myography and isolate the vasorelaxant component from M. bornmuelleri venom through bioassay-guided fractionation. We also conducted a comprehensive proteomics analysis of five Montivipera venoms. Our findings revealed that Montivipera venoms induced strong vasorelaxation of mesenteric arteries via various endothelial pathways, indicating molecules with diverse mechanisms of action. A vasorelaxant PLA2 was isolated from M. bornmuelleri venom, with effects only through endothelium-dependent pathways. Mb-PLA2, a 121-amino acid protein weighing 13,658.98 Da, was characterized, and its 3D structure revealed similarities to other PLA2s. Its vasorelaxant effect involved NO and EDHF pathways, suggesting both catalytic and non-catalytic activities.Proteomic analysis identified 129 to 179 proteins in each venom, classified into 17-19 families, including SVMPs, SVSPs, PLA2s, and svVEGFs. This study enhances the understanding of Montivipera venoms and provides valuable resources for developing species-specific antivenoms. In conclusion, the study highlights the heterogeneity of vasorelaxant molecules in Montivipera venoms, with Mb-PLA2 offering a novel mode of action for potential antihypertensive treatments.