Homeostasis of vascular vessels and prevention of atherosclerosis by vasohibin-1

Vasohibin-1（VASH 1）是一种内皮细胞（EC）产生的血管生成抑制剂。本研究探讨了VASH 1在内皮细胞中除抑制血管生成外，是否还发挥其他作用，以及VASH 1在内皮细胞中的敲低或过表达，并检测了内皮细胞特性的变化。敲低VASH 1基因可诱导内皮细胞过早衰老，并且这些内皮细胞容易被细胞应激杀死。相反，VASH 1的过表达使内皮细胞抵抗细胞应激引起的过早衰老和细胞死亡。VASH 1的合成受HuR介导的转录后调控。我们试图确定潜在的机制。VASH 1增加了（超氧化物歧化酶2）SOD 2的表达，SOD 2是一种已知的淬灭活性氧（ROS）的酶。同时，VASH 1增加了抗衰老蛋白sirtuin 1（SIRT 1）的合成，这提高了应激耐受性。更多的VASH 1（+/-）小鼠死于百草枯引起的急性肺损伤。肺内给予编码人VASH 1的腺病毒载体可增强肺内SOD 2和SIRT 1的表达，并预防百草枯引起的急性肺损伤。因此，VASH 1是提高内皮细胞SOD 2和SIRT 1诱导的应激耐受性的关键因素。

Vasohibin-1 (VASH1) is isolated as an endothelial cell (EC)-produced angiogenesis inhibitor. We questioned whether VASH1 plays any role besides angiogenesis inhibition, knocked-down or overexpressed VASH1 in ECs, and examined the changes of EC property. Knock-down of VASH1 induced premature senescence of ECs, and those ECs were easily killed by cellular stresses. In contrast, overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses. The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation. We sought to define the underlying mechanism. VASH1 increased the expression of (superoxide dismutase2) SOD2, an enzyme known to quench reactive oxygen species (ROS). Simultaneously, VASH1 augmented the synthesis of sirtuin 1 (SIRT1), an anti-aging protein, which improved stress tolerance.Paraquat generates ROS and causes organ damage when administered in vivo. More VASH1 (+/-) mice died due to acute lung injury caused by paraquat. Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat. Thus, VASH1 is a critical factor that improves the stress tolerance of ECs viathe induction of SOD2 and SIRT1.