CSE/H2S系统调控Nrf2介导线粒体融合延缓血管衰老的机制研究

The degree of vascular aging is closely linked to the body's aging. Mitochondrial cleavage protein Drp1 phosphorylation plays an important role in cardiovascular. The molecular mechanism of endogenous hydrogen sulfide (H2S) mediates the regulation of vascular aging by Drp1 is unclear. Preliminary experiment showed that the expression of the enzyme cystathionine-γ-lyase (CSE), which catalyzes the production of endogenous hydrogen sulfide in the blood vessels of aged mice, is decreased. CSE knock-out mice exhibited severe vascular aging, H2S can inhibit Drp1 expression and increase the expression of Nrf2. Our hypothesis is "Aging causes a decrease in CSE activity. Nrf2 may be involved in CSE/H2S system regulation of oxidative stress-mediated Drp1 phosphorylation induced mitochondrial fusion, and then playing a critical role in delaying vascular aging." The project focus on vascular aging: 1) Exploring the role of CSE/H2S system in vascular aging; 2) Investigating CSE/H2S system mediated Nrf2 promotion to nuclear regulation of mitochondrial fusion; 3) To study the molecular mechanism of CSE/H2S system regulating the phosphorylation of Drp1. This project is to elucidate the mechanism of CSE/H2S system regulates Nrf2 mediated Drp1 phosphorylation-switching molecular switch-induced mitochondrial fusion and to elucidate the novel way to delay vascular aging. Our research may provide new treatment targets for aging related diseases, which are of crucial practical significance for the prevention and treatment of aging related to cardiovascular disease.

血管衰老与机体衰老息息相关。线粒体分裂蛋白Drp1磷酸化转换在心血管中发挥重要作用。内源性硫化氢（H2S）介导Drp1调控血管衰老的分子机制，尚不清楚。预实验提示：老年小鼠血管中催化内源性硫化氢生成的酶胱硫醚-γ-裂解酶（CSE）表达下降；CSE敲除后，血管老化加剧。硫化氢可抑制Drp1的表达，同时提高Nrf2的表达。基于此提出研究假说“衰老引起CSE活性下降。CSE/H2S系统可能通过Nrf2调控氧化应激介导Drp1磷酸化诱导线粒体融合，延缓血管衰老”。本项目围绕血管衰老：1）研究CSE/H2S系统在血管衰老中的作用；2）研究CSE/H2S系统介导Nrf2异位入细胞核调控线粒体融合；3）研究CSE/H2S系统调控Drp1磷酸化转换的分子机制。阐明CSE/H2S系统调控Nrf2介导Drp1磷酸化转换分子开关诱导线粒体融合，延缓血管衰老的作用机制。为防治血管衰老相关疾病提供新思路和新靶点。

研究背景：人口老龄化是全世界面临的共同难题，在我国尤为严峻。血管衰老与机体衰老息息相关，心血管疾病及其危险因素引起血管衰老，继而影响其发生发展和预后。线粒体分裂蛋白Drp1磷酸化转换在心血管中发挥重要作用。内源性硫化氢（H2S）介导Drp1调控血管衰老的分子机制，尚不清楚。.研究内容：研究CSE/H2S系统在血管衰老中的作用；研究CSE/H2S系统介导Nrf2异位入细胞核调控线粒体融合；研究CSE/H2S系统调控Drp1磷酸化转换的分子机制。.研究结果：①老年小鼠血管中催化内源性硫化氢生成的酶胱硫醚-γ-裂解酶CSE表达下降；CSE敲除后，血管老化加剧。H2S水平下降在衰老中很常见，如小鼠的心，肝，肾，血液等。.②硫化氢生成酶CSE参与内皮细胞的代谢调节。衰老内皮细胞敲除CSE后，线粒体功能下降，ATP下降，且硫化氢生成酶CSE参与线粒体融合分裂的调控，如调控Mfn2，Drp1的蛋白水平。.③内源性和外源性硫化氢可以促进衰老内皮细胞增殖，迁移，管腔形成。硫化氢部分抑制衰老内皮细胞中的细胞凋亡和Caspase 家族的活性。.④硫化氢部分改善衰老内皮细胞线粒体功能和氧化应激状态。突变硫化氢生成酶活性中心（CSED187A），过表达硫化氢生成酶CSE突变体，其促进衰老内皮细胞迁移，管腔形成能力消失，对抗细胞内活性氧和线粒体中活性氧的能力消失。.⑤内源性硫化氢可以促进Nrf2在应激状态易位到细胞核，发挥抗氧化应激的作用，并且Nrf2的细胞核易位部分依赖于PI3K/Akt信号通路。应激状态时，硫化氢生成酶CSE易位到线粒体，产生硫化氢，发挥抗氧化应激的作用。.研究意义：CSE/H2S系统调控Nrf2介导Drp1磷酸化转换分子开关诱导线粒体融合，延缓血管衰老的作用机制，为开发靶向硫化氢生成酶CSE的药物提供理论信息，为防治血管衰老相关疾病提供新思路和新靶点。