Chang Chih-Yang, Chen Po-Han, Lu Shang-Chieh, Hsieh Ming-Chu, Lin Chia-Wei, Lee Hui-Ming, Jawan Bruno, Kao Ying-Hsien
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, E-Da Hospital, Kaohsiung 824, Taiwan.
Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan.
Life Sci. 2015 Dec 1;142:49-59. doi: 10.1016/j.lfs.2015.10.014. Epub 2015 Oct 21.
Propofol (PPF), an intravenous anesthetic agent, is previously reported to attenuate oxidative stress- and inflammation-induced endothelial cell dysfunction. This study investigated its effect on endothelial cell biology.
Cultured human umbilical vein endothelial cells (HUVECs) were treated with PPF and subject to measurements for nitric oxide (NO) production, autophagy flux, signal transduction, migration, and in vitro angiogenesis.
Non-cytotoxic PPF treatment was found to significantly upregulate inducible nitric oxide synthase (NOS2) but downregulate constitutive NOS3 expression. It also potentiated LPS-induced ICAM-1 overexpression and NO overproduction. Mechanistically, the PPF-activated signal transduction in PI3K/Akt, ERK1/2, p38 MAPK, and JNK pathways were involved in the PPF-driven NO overproduction. PPF exhibited a stimulatory effect on autophagy flux by increasing expression of autophagy markers including mTOR, Beclin-1, Atg5, and LC3I/II, as well as a late endosomal indicator, Rab7. However, PPF appeared to antagonize the Rab7 upregulation by LPS. Functionally, PPF enhanced in vitro migratory and angiogenic capacities of HUVECs, but this enhancement was drastically abrogated by the presence of autophagy inhibitors, indicating a pro-angiogenic contribution of PPF-enhanced autophagy in cultured HUVECs.
Our findings support the notion that PPF enhances motility and angiogenic capacity of cultured HUVECs through an autophagy-involved regulatory mechanism.
丙泊酚（PPF）是一种静脉麻醉剂，此前有报道称其可减轻氧化应激和炎症诱导的内皮细胞功能障碍。本研究调查了其对内皮细胞生物学的影响。
用丙泊酚处理培养的人脐静脉内皮细胞（HUVECs），并检测一氧化氮（NO）生成、自噬通量、信号转导、迁移和体外血管生成。
发现非细胞毒性的丙泊酚处理可显著上调诱导型一氧化氮合酶（NOS2），但下调组成型NOS3表达。它还增强了脂多糖（LPS）诱导的细胞间黏附分子-1（ICAM-1）过表达和NO过量生成。机制上，丙泊酚激活的PI3K/Akt、ERK1/2、p38丝裂原活化蛋白激酶（MAPK）和JNK信号通路参与了丙泊酚驱动的NO过量生成。丙泊酚通过增加包括雷帕霉素靶蛋白（mTOR）、Beclin-1、自噬相关蛋白5（Atg5）和微管相关蛋白1轻链3I/II（LC3I/II）等自噬标志物的表达以及晚期内体指标Rab7，对自噬通量产生刺激作用。然而，丙泊酚似乎拮抗了LPS诱导的Rab7上调。功能上，丙泊酚增强了HUVECs的体外迁移和血管生成能力，但自噬抑制剂的存在显著消除了这种增强作用，表明丙泊酚增强的自噬对培养的HUVECs有促血管生成作用。
我们的研究结果支持丙泊酚通过自噬相关调节机制增强培养的HUVECs的运动性和血管生成能力这一观点。
