“清心除热”中药莲子心介导白三烯代谢LTB4DH/12-oxo-LTB4/SH-PTP1轴抗心肌纤维化分子机制

心肌纤维化是心血管疾病发生和恶化的风险因素。莲子心有清心除热功效，中医常用于心脑血管疾病治疗。我们预实验发现莲子心总生物碱可显著抗心肌纤维化，并激活白三烯代谢关键酶LTB4DH，提高代谢物12-oxo-LTB4含量。但12-oxo-LTB4与心肌纤维的关系尚不清晰。初步发现该代谢物可与酪氨酸激酶SH-PTP1共价结合而增强巨噬细胞吞噬功能。因此我们推测莲子心可介导LTB4DH/12-oxo-LTB4/SH-PTP1白三烯代谢轴增强巨噬细胞吞噬而抑制心肌纤维化。我们拟采用心肌纤维化模型和脂质代谢组学研究莲子心抗心肌纤维化作用和对LTB4DH及代谢产物影响；采用分子探针、基因敲除、免疫共沉淀等技术确证莲子心靶向LTB4DH，促进12-oxo-LTB4与SH-PTP1结合抗心肌纤维化分子机制。本课题既可从白三烯代谢轴上揭示莲子心抗心肌纤维化新机制，也为研发靶点明确的抗心肌纤维中药新药提供依据。

Myocardial fibrosis is an important risk factor for the development and progression of cardiovascular disease. Lotus plumule has the effect of "clearing the heart and eliminating heat". It is often commonly used for treating cardio-cerebrovascular diseases in traditional Chinese medicine. Our preliminary results showed that the total alkaloid of Lotus plumule (TLA) significantly suppressed myocardial fibrosis. Interestingly, TLA could activated the leukotriene B4 12-hydroxydehydrogenas (LTB4DH) and subsequently increased the content of 12-oxo-LTB4. However, the relationship between 12-oxo-LTB4 and myocardial fibrosis remains unclear. We preliminarily found that 12-oxo-LTB4 could covalently bind with tyrosine-protein phosphatase SH-PTP1 to enhance macrophage phagocytosis, which might be a new mechanism of anti- myocardial fibrosis. Therefore, we hypothesize that the Lotus plumule enhanced macrophage phagocytosis and inhibited myocardial fibrosis via targeting LTB4DH/12-oxo-LTB4/SH-PTP1 axis. To confirm this scientific problem, we will first use the myocardial fibrosis model and the lipid metabolomics method to study the anti-myocardial fibrosis effect of Lotus plumule and its effect on LTB4DH and metabolites. Then, we will use molecular probes, chemical biology, gene knockout and immunoco-precipitated proteomics to confirm that Lotus plumule will promote 12-oxo-LTB4 binding with SH-PTP1 via targeting LTB4DH enzyme to suppress myocardial fibrosis. The expected results can not only reveal the anti-myocardial fibrosis mechanism of Lotus plumule via the leukotriene metabolism axis, but also provide a basis for the research and development of anti-myocardial fibrosis traditional Chinese medicine drugs with clear targets.