Akademik Veri Yönetim Sistemi
LIFE SCIENCES, cilt.286, 2021 (SCI-Expanded)
Objective: Endothelial dysfunction occurs as an early event in cardiovascular disease. Previously, vorapaxar, a proteinase-activated receptor-1 antagonist, was shown to cause endothelial damage in a cell culture study. Therefore, our study aimed to compare the effects of vorapaxar and parmodulin-2, proteinase-activated receptor1 biased agonist, on human left internal mammary artery endothelial function in vitro. Method: Isolated arteries were hung in the organ baths. Acetylcholine responses (10- 11-10-6 M) were obtained in endothelium-intact tissues the following incubation with vorapaxar/parmodulin-2 (10-6 M) to determine the effects of these molecules on the endothelium-dependent relaxation. Subsequently, endothelium-dependent relaxation responses of tissues were investigated in the presence of L-NAME (10-4 M), L-arginine (10-5 M), indomethacin (10- 5 M), and charybdotoxin-apamin (10-7 M) in addition to vorapaxar/parmodulin-2 incubation. Besides, the effect of these molecules on endothelium-independent relaxation response was evaluated with sodium nitroprusside (10- 11-10-6 M). Finally, the sections of human arteries were imaged using a transmission electron microscope, and the integrity of the endothelial layer was evaluated. Results: We found that vorapaxar caused significant endothelial dysfunction by disrupting nitric oxide and endothelium-derived hyperpolarizing factor-dependent relaxation mechanisms. Parmodulin-2 did not cause endothelial damage. Neither vorapaxar nor parmodulin-2 disrupted endothelium-independent relaxation responses. The effect of vorapaxar on the endothelial layer was supported by the transmission electron microscope images. Conclusion: Parmodulin-2 may be a better option than vorapaxar in treating cardiovascular diseases since it can inhibit PAR-1 without caused endothelial dysfunction.