Doctor of Philosophy (PhD) in Pharmacy
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College of Pharmacy
Ana M Castejon
Luigi X Cubeddu
Publication Date / Copyright Date
Nova Southeastern University
Varun Kumar Soti. 2019. Protective Actions of Oxytocin on Aortic Wistar and SHR VSMCs. Doctoral dissertation. Nova Southeastern University. Retrieved from NSUWorks, College of Pharmacy. (4)
Background. Oxytocin, known as a female reproductive hormone, has emerged as a cardiovascular hormone showing cardioprotective effects, for instance, negative chronotropic and inotropic effects and ANP release in cardiomyocytes and endothelium. However, oxytocin’s effect in VSMCs remains to be explored. Objectives. This study had three goals: characterizing oxytocin’s effect on proliferation, inflammation, oxidative stress, and vasocontraction pathway in Wistar VSMCs; determining oxytocin’s effect on Ang II; describing oxytocin’s effect and its interaction with Ang II in SHR VSMCs. Methods: Aortic VSMCs were isolated from Wistar rats and SHRs. Hemocytometer, MTT and 3H-Thymidine incorporation assays, and flow cytometry were employed for cell proliferation studies. Two key proliferation pathways — ERK1/2 and PI3K/Akt pathways, and vasocontraction (ROCK) pathway were investigated for mechanistic studies utilizing Western blotting. IL-6 and ROS were measured to assess inflammation and oxidative stress, respectively. Results. Cell proliferation studies and Western blotting outcomes in Wistar and SHR VSMCs demonstrated that oxytocin (100 nM) significantly decreased cell proliferation and reduced phosphorylation of ERK1/2, PI3Kp110α, Akt, ROCK-1, and ROCK-2, respectively. OXTA antagonized these effects of oxytocin. Flow cytometric measurements indicated that oxytocin-induced apoptosis and necrosis. IL-6 assay and ROS assay results displayed that oxytocin increased IL-6 and ROS, respectively. Oxytocin’s pre-treatment with Ang II in Wistar and SHR VSMCs caused: decreased cell proliferation; reduced phospho-ERK1/2, phospho-PI3Kp110α, phospho-Akt, ROCK-1, and ROCK-2; decreased IL-6; increased ROS. Comparison between Wistar and SHR VSMCs illustrated that oxytocin greatly reduced PI3Kp110α phosphorylation in Wistar VSMCs than SHR VSMCs (P < 0.01). Oxytocin caused higher IL-6 secretion in SHR VSMCs (P < 0.01) and higher ROS production in Wistar VSMCs (P < 0.001). Oxytocin’s pre-treatment with Ang II showed: higher reduction in ERK1/2 phosphorylation in SHR VSMCs (P < 0.001); higher reduction in PI3Kp110α phosphorylation (P < 0.05) and higher increase in ROS in Wistar VSMCs (P < 0.001). Conclusion. Oxytocin showed an anti-proliferative effect on aortic VSMCs, likely through inhibition of ERK1/2 and PI3K/Akt phosphorylation. Oxytocin-mediated decreased phosphorylation of ROCK-1 and ROCK-2 suggest oxytocin’s anti-vasoconstrictive action in VSMCs. Oxytocin’s antagonistic actions against Ang II indicate that oxytocin may exert beneficial vascular effects in conditions associated with high levels of Ang II.
Pharmacy and Pharmaceutical Sciences
Ang II, Aortic VSMCs, ERK 1/2, Oxytocin, PI3K/Akt, ROCK -1 and -2
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