高尿酸通过激活免疫蛋白酶体催化亚型LMP7致心肌肥厚的机制研究

高尿酸血症与心血管疾病密切相关，既往研究多关注其在动脉粥样硬化等血管损伤中作用。晚近研究发现高尿酸亦参与心肌肥厚与损伤，但分子生物学机制尚无报道。本团队研究证实免疫蛋白酶体催化亚型LMP7促进小鼠压力负荷诱导的心肌肥厚，为此我们做了前期研究探索LMP7是否参与高尿酸诱导的心肌肥厚。结果发现高尿酸诱导小鼠心肌肥厚伴心肌LMP7表达上调，敲除或抑制LMP7可降低高尿酸小鼠血清尿酸水平，抑制心肌肥厚、纤维化和炎症反应，但相关分子机制仍需深入研究。故本课题拟采用尿酸酶基因敲除小鼠构建高尿酸血症小鼠模型，并通过抑制、敲除或过表达LMP7，进一步系统研究LMP7在高尿酸性心肌肥厚中的作用。同时应用基因芯片及分子生物学手段，阐明和证实LMP7是否通过调控自噬，降解黄嘌呤脱氢酶（XDH），进而抑制高尿酸性心肌肥厚的分子机制，为高尿酸性心肌肥厚治疗提供新的靶点。

Hyperuricemia is closely associated with cardiovascular diseases such as atherosclerotic vascular injury. Previous study demonstrated immunoproteasome catalytic subunit LMP7 promoted pressure-overload induced cardiac hypertrophy in mice (Science Advances 2019), but the mechanism involved was not elucidative. We found that large multifunctional peptidase 7 (LMP 7) participate pressure-overload induced cardiac hypertrophy in previous study. But whether LMP7 participate in hyperuricemia induced cardiac hypertrophy was obscure. Our previous data demonstrated that hyperuricemia induced cardiac hypertrophy in mice accompany with increased LMP7 expression in heart tissues. Serum uric acid concentration was reduced while cardiac hypertrophy was abolished in LMP7 Knockout mice; fibrosis and inflammation with hyperuricemia were also observed in mice. We found knockout of LMP7 induced autophagic degradation of xanthine dehydrogenase (XDH) in cardiomyocytes, however, the relative molecular mechanism need be further investigated. This project is planning to use urate oxidase knockout mice to establish mice model of hyperuricemia, and then LMP7 was further inhibited, knocked out or overexpressed to investigated the role of LMP7 in hyperuricemia induced cardiac hypertrophy. The combination of gene microarrays technique and molecular/cellular approaches would assist to uncover the potential mechanisms that LMP7 regulated autophagic degradation of XDH that subsequently inhibited cardiac hypertrophy in mice with hyperuricemia. The subjective of this project is to provide important evidence for searching new target to treat hyperuricemia-induced heart failure.