期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 174, 期 17, 页码 2818-2831出版社
WILEY
DOI: 10.1111/bph.13885
关键词
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资金
- National Natural Science Foundation of China [81274131, 81601034]
- Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Jiangsu Province 2011 Plan for Collaborative Innovation
- Anhui Provincial Natural Science Foundation [1608085QH185]
- Key Project Fund for Outstanding Young Talents in Anhui Higher Education Institutions [gxyqZD2016348]
BACKGROUND AND PURPOSE Non-muscular myosin heavy chain IIA (NMMHC IIA) plays a key role in tissue factor expression and venous thrombosis. Natural products might inhibit thrombosis through effects on NMMHC IIA. Here, we have shown that a natural saponin, D39, from Liriope muscari exerted anti-thrombotic activity in vivo, by targeting NMMHC IIA. EXPERIMENTAL APPROACH Expression and activity of tissue factor in endothelial cells were analysed in vitro by Western blot and simplified chromogenic assays. Interactions between D39 and NMMHC IIA were assessed by serial affinity chromatography and molecular docking analysis. D39-dependent interactions between NMMHC IIA and TNF receptor 2 (TNFR2) were measured by immunofluorescence, co-immunoprecipitation and proximity ligation assays. Anti-thrombotic activity of D39 in vivo was evaluated with a model of inferior vena cava ligation injury in mice. KEY RESULTS D39 inhibited tissue factor expression and procoagulant activities in HUVECs and decreased thrombus weight in inferior vena cava-ligated mice dose-dependently. Serial affinity chromatography and molecular docking analysis suggested that D39 bound to NMMHC IIA. In HEK293T cells, D39 inhibited tissue factor expression evoked by NMMHC IIA overexpression. This effect was blocked by NMMHC IIA knockdown in HUVECs. D39 inhibited dissociation of NMMHC IIA from TNFR2, which subsequently modulated the Akt/GSK3 beta-NF-kappa B signalling pathways. CONCLUSIONS AND IMPLICATIONS D39 inhibited tissue factor expression and thrombus formation by modulating the Akt/GSK3 beta and NF-kappa B signalling pathways through NMMHC IIA. We identified a new natural product that targeted NMMHC IIA, as a potential treatment for thrombotic disorders and other vasculopathies.
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