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 μg/mL). We showed that pretreatment with MLB (10-100 μM) dose-dependently inhibited LPS-induced upregulation of inflammatory cytokines ICAM1, VCAM1, and TNFα, 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-κB activation through inhibition of IκBα degradation and subsequent phosphorylation of NF-κB 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 IκBα degradation and ICAM1 up-regulation, which were mimicked by PKC inhibition (Gö6983) or PI3K/Akt inhibition (LY294002). In summary, our results demonstrate that MLB inhibits NF-κB 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.

中文翻译：

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Magnesium lithospermate B 通过激活 Nrf2 通路保护内皮免受炎症引起的功能障碍。

Magnesium lithospermate B (MLB) 是丹参的活性成分，丹参是一种用于治疗心血管疾病的传统中草药。在这项研究中，我们研究了 MLB 在体外和体内对炎症诱导的内皮功能障碍的保护作用及其潜在机制。脂多糖（LPS，1 μg/mL）在体外在人真皮微血管内皮细胞（HMEC-1）中诱导内皮功能障碍。我们发现用 MLB (10-100 μM) 预处理剂量依赖性地抑制 LPS 诱导的炎性细胞因子 ICAM1、VCAM1 和 TNFα 的上调，这有助于减少白细胞粘附和减弱 HMEC-1 细胞中的内皮细胞渗透性过高。SD大鼠注射LPS（10mg/kg，ip）以在体内诱导内皮功能障碍。我们表明，用 MLB (25-100 mg/kg, ip) 预处理可剂量依赖性地恢复 LPS 受损的肠系膜上动脉 (SMA) 内皮依赖性血管舒张，减弱肠系膜小静脉中的白细胞粘附并减少肺中的血管渗漏。我们进一步阐明了 MLB 保护作用的潜在机制，并揭示 MLB 预处理通过在体外和体内抑制 IκBα 降解和随后的 NF-κB p65 磷酸化来抑制 NF-κB 活化。在 HMEC-1 细胞中，MLB 预处理激活了核因子 erythroid-2 相关因子 2 (Nrf2) 通路。用 siRNA 敲低 Nrf2 消除了 MLB 对 IκBα 降解和 ICAM1 上调的抑制作用，这可以通过 PKC 抑制（Gö6983）或 PI3K/Akt 抑制（LY294002）模拟。总之，