Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
Division of Pharmacokinetic, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
Eur J Pharmacol. 2017 Nov 15;815:462-469. doi: 10.1016/j.ejphar.2017.09.042. Epub 2017 Sep 30.
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 (60nM) 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.
内皮功能障碍在肺动脉高压（PH）期间肺血管发生的结构重塑中起着重要作用。内皮损伤导致内皮细胞凋亡和激活。然而，一些内皮细胞表现出抗凋亡性，随后广泛增殖，导致血管病变和 PH 中丛状病变的形成。研究表明，快速增殖的细胞表现出脂肪酸合酶（FAS）表达增加，FAS 是一种负责脂肪酸产生的调节酶。我们之前的研究表明，FAS 抑制可防止平滑肌细胞增殖，逆转肺动脉重构，并改善野百合碱诱导的 PH 模型中的肺血管反应性。然而，FAS 在肺动脉内皮细胞增殖和血管生成中的作用尚未得到探索。本研究旨在探讨 FAS 在与 PH 相关的内皮功能障碍中的增殖、代谢功能障碍和血管生成中的作用。将人肺动脉内皮细胞（HPAEC）暴露于低氧环境中，并使用 FAS siRNA（60nM）抑制 FAS。在低氧 HPAEC 中观察到 FAS 的表达和活性增加。FAS 抑制增加了低氧 HPAEC 中的细胞凋亡和葡萄糖氧化，但降低了细胞增殖、自噬和糖酵解的标志物。FAS 抑制降低了低氧 HPAEC 中的血管生成，表现为管腔长度和 VEGF 表达减少。FAS 抑制还增加了低氧 HPAEC 中内皮型一氧化氮合酶的表达，这是内皮功能的标志物。我们的结果证明并进一步支持了之前的发现，即 FAS 抑制有利于肺动脉高压中的内皮功能。
