Department of Cardiology, Jinhua People's Hospital, Jinhua, Zhejiang 321000, P.R. China.
Mol Med Rep. 2020 Aug;22(2):1351-1361. doi: 10.3892/mmr.2020.11207. Epub 2020 Jun 3.
Myocardial ischemia‑reperfusion (MI/R) injury is a complex pathological process that occurs when tissues are reperfused following a prolonged period of ischemia. Troxerutin has been reported to have cardioprotective functions. However, the underlying mechanism by which troxerutin protects against MI/R injury has not been fully elucidated. The aim of the present study was to explore whether troxerutin‑mediated protection against oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced H9C2 cell injury was associated with the inhibition of oxidative stress and the inflammatory response by regulating the PI3K/AKT/hypoxia‑inducible factor‑1α (HIF‑1α) signaling pathway. The results of the present study suggested that troxerutin pretreatment prevented the OGD/R‑induced reduction in cell viability, and the increase in lactate dehydrogenase activity and apoptosis. Troxerutin reversed OGD/R‑induced the inhibition of the PI3K/AKT/HIF‑1α signaling pathway as demonstrated by the increased expression of PI3K and HIF‑1α, and the increased ratio of phosphorylated AKT/AKT. LY294002, a selective PI3K inhibitor, inhibited the PI3K/AKT/HIF‑1α signaling pathway and further attenuated the protective effect of troxerutin against OGD/R‑induced H9C2 cell damage. Furthermore, small interfering (si)RNA‑mediated knockdown of HIF‑1α reduced troxerutin‑induced protection against OGD/R injury. Troxerutin pretreatment alleviated OGD/R‑induced oxidative stress, as demonstrated by the reduced generation of reactive oxygen species and malonaldehyde content, and the increased activities of superoxide dismutase and glutathione peroxidase, which were reduced by HIF‑1α‑siRNA. Troxerutin‑induced decreases in the levels of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α in OGD/R conditions were also reduced by HIF‑1α‑siRNA. The results from the present study indicated that troxerutin aggravated OGD/R‑induced H9C2 cell injury by inhibiting oxidative stress and the inflammatory response. The primary underlying protective mechanism of troxerutin was mediated by the activation of the PI3K/AKT/HIF‑1α signaling pathway.
心肌缺血再灌注（MI/R）损伤是组织在长时间缺血后再灌注时发生的一种复杂的病理过程。曲克芦丁已被报道具有心脏保护功能。然而，曲克芦丁保护心肌免受 MI/R 损伤的机制尚未完全阐明。本研究旨在探讨曲克芦丁是否通过调节 PI3K/AKT/缺氧诱导因子-1α（HIF-1α）信号通路来抑制氧化应激和炎症反应，从而对氧葡萄糖剥夺/复氧（OGD/R）诱导的 H9C2 细胞损伤起保护作用。本研究结果表明，曲克芦丁预处理可防止 OGD/R 诱导的细胞活力降低和乳酸脱氢酶活性及凋亡增加。曲克芦丁逆转了 OGD/R 诱导的 PI3K/AKT/HIF-1α 信号通路的抑制，表现为 PI3K 和 HIF-1α 的表达增加，以及磷酸化 AKT/AKT 的比值增加。PI3K 选择性抑制剂 LY294002 抑制了 PI3K/AKT/HIF-1α 信号通路，进一步减弱了曲克芦丁对 OGD/R 诱导的 H9C2 细胞损伤的保护作用。此外，小干扰 RNA（siRNA）介导的 HIF-1α 敲低降低了曲克芦丁对 OGD/R 损伤的保护作用。曲克芦丁预处理减轻了 OGD/R 诱导的氧化应激，表现为活性氧和丙二醛含量减少，超氧化物歧化酶和谷胱甘肽过氧化物酶活性增加，而这些作用均被 HIF-1α-siRNA 减弱。曲克芦丁诱导的 OGD/R 条件下白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子-α水平的降低也被 HIF-1α-siRNA 减弱。本研究结果表明，曲克芦丁通过抑制氧化应激和炎症反应加重 OGD/R 诱导的 H9C2 细胞损伤。曲克芦丁的主要保护机制是通过激活 PI3K/AKT/HIF-1α 信号通路来介导的。
