Article

Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway

Authors: Fei Gao1,2, Jiao-meng Li1,2, Cong Xi1,2, Hui-hui Li1,2, Ying-luo Liu1,2, Yi-ping Wang1,2, Li-jiang Xuan1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
2 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Li-jiang Xuan: ljxuan@simm.ac.cn,
DOI: 10.1038/s41401-018-0189-1
Received: 12 June 2018
Accepted: 18 October 2018
Advance online: 7 January 2019

Abstract

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.
Keywords: magnesium lithospermate B; endothelium; human dermal microvascular endothelial cells; rat superior mesenteric artery rings; lipopolysaccharide; inflammation; Nrf2; PKC; PI3K/Akt

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