Involvement of S100A4/Mts1 and associated proteins in the protective effect of fluoxetine against MCT - Induced pulmonary hypertension in rats

Background: Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by remodeling of the pulmonary vessels and a persistent increase in the pulmonary vascular resistance (PVR) with a poor prognosis. Serotonin increases the expression of S100A4/Mtsl, which in turn stimulates the proliferation and migration of human pulmonary artery smooth muscle cells through the interaction with RAGE (receptor for advanced glycation end products) and thus S100A4/Mts1 has been implicated in the development of PAH in vitro. Fluoxetine, a selective serotonin re-uptake inhibitor has been shown to protect against PAH. The current study was designed to test whether S100A4 and its associated proteins connected in the development of PAH in vivo as well as to investigate the involvement of those proteins in the protective effect of fluoxetine against PAH. Methods: MCT-induced PAH models were established in Wistar rats by a single intraperitoneal injection of MCT (60 mg/kg). Fluoxetine (2 and 10 mg/kg/day) was intragastrically administered once a day for 3 weeks along with controls. The detection methods followed include Hematoxylin and Eosin (H&E) staining, immunohistochemistry, western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: MCT induced pulmonary hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy significantly increased the expressions of S100A4 and RAGE in the pulmonary arteries, lungs and right ventricle (RV). Fluoxetine dose-dependently inhibited MCTinduced pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy and reduced the 5100A4 and RAGE. Further analysis revealed that fluoxetine alleviated both the increase of p53, MMP13, MMP2 and MMP9 and the decrease of pp53Ser15 and MDM2 in lungs and RV tissues of MCT-induced PAH rats. Conclusion: From the present investigation it could be concluded that S100A4/Mts1 and its associated proteins are involved in the evolution of MCT-induced PAH in rats and fluoxetine inhibits MCT-induced PAH in rats mainly through S100A4/RAGE signaling axis and involved factors. Copyright (C) 2018, the Chinese Medical Association. Published by Elsevier Taiwan LLC.