P682Primate specific gene, POTEE has a protective role against vascular injury in endothelial cells

Abstract

Background: Chronic exposure to cellular stress induces time-dependent, irreversible cellular damage characterised by cellular senescence. The senescent cells cause inflammation via the production of pro-inflammatory molecules, leading to the acquisition of the Senescence-Associated Secretory Phenotype, which is associated with the development of age-related diseases. The pathogenesis of atherosclerosis is also characterised by stress induced vascular senescence and inflammation. Humans have several innate protective mechanisms to prevent cellular damage from stress; however, the potency of these innate mechanisms varies between individuals. In rare cases, patients suffering from a strong exposure to cellular stress exhibit minimal organ damage, which suggests that those patients have strong innate protective mechanisms. Although there are several methods of genetic analysis, including genome-wide association study and exome sequencing, the athero-protective mechanisms are still unknown. Primate specific gene, POTEE has been reported to express in some cancers, however, its function is poorly understood. In mammals, lifespan can be correlated with body weight. However, primates have markedly longer lifespans than this correlation would suggest. It suggests some primate specific genes contribute to extend life span through attenuation of stress responses including cellular senescence and inflammation. Purpose: We used induced pluripotent stem cells (iPSCs)-derived endothelial cells (ECs) to explore innate athero-protective mechanisms. Then, we clarify the roles of POTEE as a molecular target of anti-atherosclerosis Methods and results: We selected severely diabetic patients with minimal vascular damage, and classified them as atherosclerosis resistant (Athero-R), and patients with extensive vascular damage, and classified them as atherosclerosis sensitive (Athero-S). We generated iPSCs and differentiated them into ECs (Athero-R- and Athero-S-iPSC-ECs). Athero-R-iPSC-ECs showed an attenuated stress response, which includes reduced inflammation and cellular senescence. To explore the mechanism of anti-inflammation in Athero-R-iPSC-ECs, we performed transcriptome analyses using microarray, and found POTEE is highly expressed in those cells. Next we examined POTEE function by overexpression in HUVEC. POTEE negatively regulates the cellular stress responses through nuclear factor-kappa B (NFkB) signal attenuation. Moreover, proteome and pathway analyses revealed that POTEE enhanced RAN-GTP hydrolysis and NFkB export to cytosol by direct association. Finally, the function of POTEE was examined in vivo using POTEE-overexpressed mice with femoral artery cuff-injury model, and revealed POTEE also suppressed vascular injury in vivo model. Conclusions: Our data show that POTEE plays a protective role through the regulation of Ran GTPase-NFkB pathway that would otherwise lead to cellular stress and vascular damage.