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，凋亡产生蛋白(APOP)。小鼠APOP-1的表达通过将细胞色素c从线粒体释放到胞浆间隙，继而激活caspase-9和-3，从而诱导细胞凋亡。Bax/Bak依赖的通道阻断剂Bc1-2或Bclxl不能阻断APOP-1诱导的细胞凋亡，而通透性转换孔抑制剂环孢素A则能完全阻断APOP-1诱导的细胞凋亡。缺乏CypD的细胞对APOP诱导的细胞凋亡具有抵抗力。此外，抑制APOP的表达可以阻止诱导凋亡物质诱导的细胞死亡。因此，我们的发现表明APOP-1的表达通过CypD依赖的途径诱导细胞凋亡，并且在生理条件下APOP-1在细胞死亡中发挥作用。糖尿病患者的血管老化速度加快。然而，潜在的机制仍不清楚。在这里，我们还表明，高糖诱导了凋亡信号调节激酶…的激活More Se 1(ASK1)，一种介导高血糖诱导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(HUVECs)ASK1表达水平和活性呈时间依赖性增加。内皮细胞与高糖孵育可增加细胞表达衰老相关β-半乳糖苷酶(SA-β-GAL)活性的细胞比例，而携带显性阴性ASK1基因的腺病毒载体可显著抑制高糖诱导的SA-β-GAL活性。此外，感染表达固有活性ASK1基因的腺病毒载体可直接诱导SA-β-Gal活性水平的增加。ASK1信号的激活也增强了血管内皮细胞纤溶酶原激活物抑制物-1(PAI-1)的表达。链脲佐菌素(SIZ)糖尿病小鼠可诱导动脉内皮细胞衰老，血浆PAI-1水平升高，而ASK1基因敲除小鼠可减弱STZ诱导的这些变化。我们的结果表明，高血糖通过激活ASK1信号加速内皮细胞衰老和PAI-1表达上调。因此，ASK1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。较少

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