基于IL-33/ST2-NF-κB通路探讨丹参乙酸镁MLB改善尿毒症毒素硫酸吲哚酚致心肌纤维化的作用及机制研究

心血管疾病（CVD）是终末期肾病（ESRD）患者的首要死因，心肌纤维化是该人群CVD发生发展的重要病理学基础。尿毒症毒素是ESRD人群突出的特异性致病因素，其中硫酸吲哚酚（IS）对心血管系统致病作用备受关注。我们前期研究和文献报道均证实：肾功能下降时，IS可促进心肌纤维化。预实验证实IS促进尿毒症小鼠心肌纤维化的同时，伴有IL-33/ST2通路表达上调及NF-κB活化；体外实验显示IS促进心肌成纤维细胞分泌细胞外基质。丹参乙酸镁（MLB）是有抗心肌纤维化作用的心血管保护药物，NF-κB为MLB和IL-33/ST2通路的下游分子机制。推测ESRD患者中MLB通过IL-33/ST2通路介导下调NF-κB，改善心肌纤维化。本项目通过体内外模型，采用基因敲除、IL-33干预等方法，阐明MLB通过IL-33/ST2通路介导改善IS诱导心肌纤维化的机制，为ESRD患者优化诊治提供新的药物干预措施。

Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD), and myocardial fibrosis is a key pathological presentation of CVD in this population. Uremic toxins are prominent pathogenic factors in the ESRD population. Indoxyl sulfate (IS) is a potential cardiovascular pathogenic factor. Previous studies have confirmed that IS promotes myocardial fibrosis in patients with renal dysfunction. Preliminary studies confirmed that IS induced myocardial fibrosis in uremic mice with upregulation of IL-33/ST2 pathway expression and NF-κB activation; in vitro experiments showed that IS promoted extracellular matrix secretion by cardiac fibroblasts.  Magnesium lithospermate B (MLB) is a cardioprotective drug with anti-myocardial fibrosis effect, and NF-κB is the downstream molecular mechanism of MLB and IL-33/ST2 pathway. It is hypothesized that MLB interacts with IL-33/ST2 pathway to regulate NF-κB and ameliorate myocardial fibrosis in ESRD patients. This study aims to elucidate the mechanism of MLB interacting with IL-33/ST2 pathway to ameliorate IS-induced myocardial fibrosis, using ex vivo model with gene knockout and IL-33 intervention. Thus providing potential pharmacological interventions for the optimal management of ESRD patients.