Fatty acid synthase modulates proliferation, metabolic functions and angiogenesis in hypoxic pulmonary artery endothelial cells

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Endothelial dysfunction plays an important role in structural remodeling occurring in the pulmonary vasculature during pulmonary hypertension (PH). Endothelial injury causes apoptosis and activation of endothelial cells. However, some endothelial cells show apoptosis-resistance and later proliferate extensively leading to vascular oculopathy and formation of plexiform lesions in PH. Studies have shown that rapidly proliferating cells exhibit increased expression of Fatty acid synthase (FAS), a regulatory enzyme responsible for the production of fatty acids. Our previous study has shown that FAS inhibition prevented smooth muscle cell proliferation, reversed pulmonary vascular remodeling and improved pulmonary vasoreactivity in monocrotaline induced PH model. However, the role of FAS in pulmonary artery endothelial cell proliferation and angiogenesis has not been explored. The present study was designed to explore the role of FAS in proliferation, metabolic dysfunctions, and angiogenesis in endothelial dysfunction associated with PH. The human pulmonary artery endothelial cells (HPAECs) were exposed to hypoxia and FAS siRNA (60 nM) was used for the FAS inhibition. Increased expression and activity of FAS were observed in hypoxic HPAECs. Inhibition of FAS increased apoptosis and glucose oxidation, but decreased cellular proliferation, markers of autophagy and glycolysis in hypoxic HPAECs. FAS inhibition decreased the angiogenesis as evident by decreased tubule length and VEGF expression in hypoxic HPAECs. Inhibition of FAS also increased expression of endothelial NOS in hypoxic HPAECs, a marker of endothelial function. Our results proved, and further supported previous findings, that inhibition of FAS is beneficial for endothelial function in pulmonary hypertension.

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