组蛋白去乙酰化酶HDAC8调节原肌球蛋白TPM3巴豆酰化修饰对血管舒张的作用及机制研究

高血压是重大公共卫生问题，探索机制和发现药物新靶点具有重要意义。申请人前期发现组蛋白去乙酰化酶抑制剂(HDACi)通过抑制组蛋白去乙酰化酶HDAC作用显著舒张血管主动脉，但确切机制尚不清楚。我们深入研究发现巴豆酸显著舒张血管平滑肌，原肌球蛋白TPM3的巴豆酰化与TPM3-HDAC8相互作用受到苯肾上腺素调控。申请人提出HDAC8通过调节TPM3巴豆酰化蛋白修饰可能是HDACi舒张血管的作用机制假说。调节TPM3巴豆酰化舒张血管机制和以HDAC8为靶标的高血压治疗药物未见报道。本申请拟在前期研究基础上：明确巴豆酰化TPM3促进高血压血管平滑肌舒张作用；阐明HDAC8-TPM3-actin通路在高血压血管异常收缩中作用机制；研究HDAC8选择性抑制剂对高血压模型降血压作用，发掘新靶点。本研究将有助于阐明血管平滑肌舒缩机制，为研发基于HDAC为靶点的高血压治疗新药物提供科学依据。

Hypertension is major public health issue. Digging the potential anti-hypertensive targets and investigating the potential anti-hypertensive drugs have great significance. We have previously found that histone deacetylase inhibitors (HDACi) significantly relax aorta, though its mechanisms remain unknown. Further evidence showed that crotonic acid could remarkably relax aorta. Moreover, TPM3 (tropomyosin 3) crotonylation and HDAC8-TPM3 interaction could be mediated by phenylephrine. We hypothesize that suppressing HDAC8 induce vasodilation of aorta may through up-regulation of TPM3 crotonylation. It is not very clear that whether crotonylation of TPM3 could mediate vasodilation, and very few drugs could treat it in clinical. The molecular mechanisms underlying the HDACi in treatment of hypertension are unclear. Based on our previous studies, here we will further investigate the function of TPM3 crotonylation in hypertensive vasoconstriction. Next, we will understand the mechanism of HDAC8-TPM3-actin pathway in hypertensive vasoconstriction and exploit the potential application of HDACi in cardiovascular diseases. Our study will provide the scientific evidence on the mechanism of vasodilation and provide a potential strategy of the HDACi on treating hypertension.