HO-1对血管内皮细胞应激性衰老的调控机制

血管内皮细胞应激性衰老可导致内皮功能障碍，进而引发动脉粥样硬化等血管性疾病。前期研究发现血红素加氧酶-1（HO-1）对内皮功能有显著的保护作用，并初步证实其对内皮应激性衰老有确切的调控作用：HO-1表达在衰老内皮细胞中反馈性上调；诱导HO-1改善、siRNA干扰HO-1加剧内皮衰老。本项目拟在此基础上深入研究HO-1对内皮应激性衰老的调控机制。有证据表明内皮应激性衰老与氧化应激及mTOR通路过度激活密切相关。本课题将从调节氧化应激、mTOR信号途径的角度深入研究HO-1的调控机制，探讨HO-1调节端粒、DNA氧化损伤的作用，以及调节线粒体功能、改善细胞能量代谢的作用；探讨HO-1对mTOR信号转导途径（特别是mTORC2）的调节影响。并将在ApoE-/-小鼠动脉粥样硬化模型上验证HO-1对内皮衰老的作用和机制，为将HO-1作为防治动脉粥样硬化等心脑血管疾病的潜在作用靶标提供充足的实验依据。

Endothelial senescence is the onset of endothelial dysfunction and the main cause of several cardiovascular diseases like atherosclerosis. In our previous observations, up-regulation of heme oxygenase-1 (HO-1) prevented vascular endothelial dysfunction and protected the endothelial cells from stress-induced premature senescence. Expressions of HO-1 were up-regulated in senescent endothelial cells. Induction of HO-1 prevented stress-induced senescence, while silencing HO-1 gene exacerbated senescence in vascular endothelial cells. Based on these observations, the present study will focus on the mechanisms that HO-1 regulates cellular senescence. Since endothelial senescence is associated with oxidative stress, the effects of HO-1 on oxidative stress-induced telomere damage and DNA damage, and the effects of HO-1 on cellular metabolic dysfunction caused by mitochondrial dysfunction, will be investigated. In addition, since over-activation of mTOR signaling is a key mechanism leading to endothelial senescence, the effect of HO-1 on the mTOR signaling pathway, in particular the mTORC2-Akt pathway, will be studied. Moreover, the possible protective effect of HO-1 induction against endothelial senescence and dysfunction will be investigated in vivo in an ApoE-/- mice atherosclerosis model. The present study will pave the way to design selective pharmacological inducers of HO-1 as a potential therapeutic strategy for treating endothelial dysfunction in cardiovascular diseases.