Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway
Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway
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DOI：
10.1038/s41401-018-0189-1
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发表时间：
2019-07-01
影响因子：
8.2
通讯作者：
Xuan, Li-jiang
中科院分区：
文献类型：
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作者：
Gao, Fei;Li, Jiao-meng;Xuan, Li-jiang
紫草酸镁B（MLB）是中药丹参的有效成分，用于治疗心血管疾病。本研究旨在探讨MLB在体内外对炎症诱导的内皮功能障碍的保护作用及其机制。内皮功能障碍诱导人真皮微血管内皮细胞（HMEC-1）在体外由脂多糖（LPS，1 μ g/mL）。我们发现，预处理与MLB（10-100 μ M）剂量依赖性地抑制LPS诱导的炎症细胞因子ICAM 1，VCAM 1和TNF α，这有助于减少白细胞粘附和衰减内皮细胞高通透性HMEC-1细胞的上调。SD大鼠腹腔注射LPS（10 mg/kg），诱导内皮功能障碍。结果表明，MLB（25-100 mg/kg，ip）预处理剂量依赖性地恢复LPS损伤的上级肠系膜动脉（SMA）内皮依赖性血管舒张功能，减弱肠系膜微静脉白细胞粘附，减少肺血管渗漏。我们进一步阐明了MLB保护作用的潜在机制，并揭示了MLB预处理通过抑制I kappa Ba降解和随后的NF-κ B p65磷酸化来抑制NF-κ B B活化。在HMEC-1细胞中，MLB预处理激活核因子红细胞-2相关因子2（Nrf 2）通路。用siRNA敲低Nrf 2消除了MLB对I kappa Ba降解和ICAM 1上调的抑制作用，这通过PKC抑制（Go 6983）或PI 3 K/Akt抑制（LY 294002）来模拟。总之，我们的研究结果表明，MLB抑制NF-κ B B的激活，通过PKC和PI 3 K/Akt介导的Nrf 2激活HMEC-1细胞，并防止LPS诱导的内皮功能障碍，在小鼠模型的急性炎症。
Magnesium lithospermate B (MLB) is an active component of Salvia miltiorrhiza Radix, a traditional Chinese herb used in treating cardiovascular diseases. In this study, we investigated the protective effects of MLB against inflammation-induced endothelial dysfunction in vitro and in vivo, and the underlying mechanisms. Endothelial dysfunction was induced in human dermal microvascular endothelial cells (HMEC-1) in vitro by lipopolysaccharide (LPS, 1 mu g/mL). We showed that pretreatment with MLB (10-100 mu M) dose-dependently inhibited LPS-induced upregulation of inflammatory cytokines ICAM1, VCAM1, and TNF alpha, which contributed to reduced leukocytes adhesion and attenuation of endothelial hyperpermeability in HMEC-1 cells. SD rats were injected with LPS (10 mg/kg, ip) to induce endothelial dysfunction in vivo. We showed that pretreatment with MLB (25-100 mg/kg, ip) dose-dependently restored LPS-impaired endothelial-dependent vasodilation in superior mesenteric artery (SMA), attenuated leukocyte adhesion in mesenteric venules and decreased vascular leakage in the lungs. We further elucidated the mechanisms underlying the protective effects of MLB, and revealed that MLB pretreatment inhibited NF-kappa B activation through inhibition of I kappa Ba degradation and subsequent phosphorylation of NF-kappa B p65 in vitro and in vivo. In HMEC-1 cells, MLB pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Knockdown of Nrf2 with siRNA abolished the inhibitory effects of MLB on I kappa Ba degradation and ICAM1 up-regulation, which were mimicked by PKC inhibition (Go6983) or PI3K/Akt inhibition (LY294002). In summary, our results demonstrate that MLB inhibits NF-kappa B activation through PKC- and PI3K/Akt-mediated Nrf2 activation in HMEC-1 cells and protects against LPS-induced endothelial dysfunction in murine model of acute inflammation.