Tongxinluo inhibits cyclooxygenase-2, inducible nitric oxide synthase, hypoxia-inducible factor-2α/vascular endothelial growth factor to antagonize injury in hypoxia-stimulated cardiac microvascular endothelial cells.
Tongxinluo inhibits cyclooxygenase-2, inducible nitric oxide synthase, hypoxia-inducible factor-2α/vascular endothelial growth factor to antagonize injury in hypoxia-stimulated cardiac microvascular endothelial cells.
复制标题
通心络抑制环氧合酶2、诱导型一氧化氮合酶、缺氧诱导因子2α/血管内皮生长因子以对抗缺氧刺激的心脏微血管内皮细胞损伤
DOI：
10.4103/0366-6999.155119
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发表时间：
2015-04-20
影响因子：
6.1
通讯作者：
Tian Y
中科院分区：
文献类型：
--
作者：
Li YN;Wang XJ;Li B;Liu K;Qi JS;Liu BH;Tian Y
内皮功能障碍被认为是心血管疾病的发生过程和病理基础。环加氧酶-2 (COX-2) 和前列环素合酶 (PGIS)、诱导型一氧化氮合酶 (iNOS) 和内皮型一氧化氮合酶 (eNOS) 是在炎症和氧化应激中具有相反作用的关键酶，被认为是内皮功能障碍的主要驱动因素。在缺氧（Hx）下，Hx诱导因子（HIF）-1α和HIF-2α主要被诱导激活血管内皮生长因子（VEGF），导致异常增殖。通心络 (TXL) 是否以及如何调节 Hx 刺激的人心脏微血管内皮细胞 (HCMEC) 中的 COX-2、PGIS、iNOS、eNOS、HIF-1α、HIF-2α 和 VEGF 尚未阐明。用CoCl2模拟Hx处理HCMEC，首先确定COX-2、PGIS、iNOS、eNOS、HIF-1α、HIF-2α和VEGF的mRNA表达，然后评估不同浓度TXL处理后它们的mRNA表达和蛋白含量以及细胞病理改变。此外，还采用炎症效应分子前列腺素E2（PGE2）和氧化标记物硝基酪氨酸（NT）来反映HCMEC损伤。 Hx 可以诱导 HCMEC 中 COX-2、iNOS、HIF-2α 和 VEGF 的时间依赖性增加。基于Hx诱导的增加，TXL主要以浓度依赖性方式降低COX-2、iNOS、HIF-2α和VEGF，对PGIS和eNOS的增加作用有限。它们的蛋白质含量验证了mRNA表达的变化，这与细胞形态的变化一致。此外，高剂量TXL可以抑制Hx诱导的PGE2和NT含量增加，减轻炎症和氧化损伤。 TXL 可以抑制炎症相关的 COX-2、氧化应激相关的 iNOS 和 HIF-2α/VEGF，从而拮抗 Hx 诱导的 HCMEC 损伤。
Endothelial dysfunction is considered as the initiating process and pathological basis of cardiovascular disease. Cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS), inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) are key enzymes with opposing actions in inflammation and oxidative stress, which are believed to be the major driver of endothelial dysfunction. And in hypoxia (Hx), Hx-inducible factor (HIF)-1α and HIF-2α are predominantly induced to activate vascular endothelial growth factor (VEGF), resulting in abnormal proliferation. Whether and how Tongxinluo (TXL) modulates COX-2, PGIS, iNOS, eNOS, HIF-1α, HIF-2α, and VEGF in Hx-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been clarified. HCMEC were treated with CoCl2 to mimic Hx and the mRNA expressions of COX-2, PGIS, iNOS, eNOS, HIF-1α, HIF-2α, and VEGF were first confirmed, and then their mRNA expression and protein content as well as the cell pathological alterations were evaluated for TXL treatment with different concentrations. In addition, the effector molecular of inflammation prostaglandin E2 (PGE2) and the oxidative marker nitrotyrosine (NT) was adopted to reflect HCMEC injury. Hx could induce time-dependent increase of COX-2, iNOS, HIF-2α, and VEGF in HCMEC. Based on the Hx-induced increase, TXL could mainly decrease COX-2, iNOS, HIF-2α, and VEGF in a concentration-dependent manner, with limited effect on the increase of PGIS and eNOS. Their protein contents verified the mRNA expression changes, which was consistent with the cell morphological alterations. Furthermore, high dose TXL could inhibit the Hx-induced increase of PGE2 and NT contents, attenuating the inflammatory and oxidative injury. TXL could inhibit inflammation-related COX-2, oxidative stress-related iNOS, and HIF-2α/VEGF to antagonize Hx-induced HCMEC injury.