Basic and clinical research of a novel atherosclerosis-specific gene for the promotion of health science

在这里，我们描述了一种新的和进化上保守的蛋白质，Apop。小鼠Apop-1表达通过将细胞色素c从线粒体释放到胞质空间中，随后激活半胱天冬酶-9和-3来诱导凋亡性死亡。Apop-1诱导的细胞凋亡不被Bax/Bak依赖性通道的抑制剂Bc 1 -2或Bcl-xL阻断，而被渗透性转换孔的抑制剂环孢菌素A完全阻断。缺乏CypD的细胞对Apop诱导的凋亡具有抗性。此外，抑制Apop表达防止了由凋亡诱导物质诱导的细胞死亡。因此，我们的研究结果表明，Apop-1的表达通过CypD依赖性途径诱导细胞凋亡，并且Apop-1在生理条件下在细胞死亡中起作用。糖尿病患者的血管老化加速。然而，其潜在机制仍不清楚。在此，我们还发现高糖诱导凋亡信号调节激酶的激活， ...更多信息 se 1（ASK 1），一种介导高血糖诱导的内皮细胞衰老的凋亡诱导信号。高糖诱导人脐静脉内皮细胞（HUVEC）中ASK 1表达水平及其活性呈时间依赖性增加。内皮细胞与高糖孵育增加了表达衰老相关β-半乳糖苷酶（SA-β-gal）活性的细胞比例。然而，用包含显性阴性形式的ASK 1基因的腺病毒构建体转染显著抑制了高糖诱导的SA-β-gal活性。此外，用表达组成型活性ASK 1基因的腺病毒构建体感染直接诱导SA-β-gal活性水平的增加。ASK 1信号的激活也增强了HUVECs中纤溶酶原激活物抑制剂-1（派-1）的表达。在链脲佐菌素（SIZ）糖尿病小鼠中观察到血管内皮细胞衰老和血浆派-1水平升高的诱导，而在ASK 1基因敲除小鼠中STZ诱导的这些变化减弱。我们的研究结果表明，高血糖加速内皮细胞衰老和上调派-1的表达，通过激活ASK 1信号。因此，ASK 1可能成为预防糖尿病患者血管老化和血栓形成的新的治疗靶点。少

Here, we describe a novel and evolutionarily conserved protein, apoptogenic protein (Apop). Mouse Apop-1 expression induces apoptotic death by releasing cytochrome c from mitochondria into the cytosolic space followed by activation of caspase-9 and -3. Apop-1-induced apoptosis is not blocked by Bc1-2 or Bcl-xL, inhibitors of Bax/Bak-dependent channels, whereas it is completely blocked by cyclosporin A, an inhibitor of permeability transition pore. Cells lacking CypD were resistant to Apop-induced apoptosis. Moreover inhibition of Apop expression prevented the cell death induced by apoptosis-inducing substances. Our findings, thus, indicate that the expression of Apop-1 induces apoptosis though CypD-dependent pathway and that Apop-1 plays roles in cell death under physiological conditions. Vascular ageing is accelerated in patients with diabetes. However, the underlying mechanism remains unclear. Here, we also show that high glucose induces activation of apoptosis signal-regulating kina … More se 1(ASK1), an apoptosis-inducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a time-dependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial sells with high glucose increased the proportion of cells expressing senescence-associated beta-galactosidase (SA-beta-gal) activity However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-beta-gal activity induced by high glucose. In addition, infection with an adenoviral construct expressing the constitutively active ASK1 gene directly induced an increase in the levels of SA-beta-gal activity. Activation of the ASK1 signal also enhanced plasminogen activator inhibitor-1 (PAI-1) expression in HUVECs. Induction of senescent endothelial cells in aortas and elevation of plasma PAI-1 levels were observed in streptozotocin (SIZ) diabetic mice, whereas these changes induced by STZ were attenuated in ASK1-knockout mice. Our results suggest that hyperglycemia accelerates endothelial cell senescence and upregulation of PAI-1 expression through activation of the ASK1 signal. Thus, ASK1 may be a new therapeutic target to prevent vascular ageing and thrombosis in diabetic patients. Less