Abstract
Cell cycle slowdown or arrest is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCFSkp2 ubiquitin ligase, is a key regulator of G1/S transition. We investigated whether Skp2 plays a role in the regulation of endothelial progenitor cell (EPC) senescence, which is closely associated with aging-related vasculopathy. Replication-induced senescent EPCs demonstrated more pronounced senescence markers and lower Skp2 levels in comparison with those of their younger counterparts. Depletion of Skp2 induced increases in senescence-associated β-galactosidase (SA-βGal) activity and a reduction of telomere length and generated a senescent bioenergetics profile, whereas adenoviral-mediated Skp2 expression reversed the relevant senescence. EPCs isolated from older rats displayed a reduced proliferation rate and increased SA-βGal activity, both of which were significantly reversed by Skp2 ectopic expression. In addition to reversing senescence, Skp2 also rescued the angiogenic activity of senescent EPCs in the ischemic hind limbs of nude mice. The results revealed that ectopic expression of Skp2 has the potential to rejuvenate senescent EPCs and rescue their angiogenic activity and thus may be pivotal in the development of novel strategies to manage aging-related vascular disease.
Highlights
Advanced age is a strong and independent risk factor for the development of atherosclerosis-related diseases
Because Skp[2] is a major regulator of G1/S transition in many cell types, we investigated whether it plays a role in replication-induced endothelial progenitor cell (EPC) senescence
Because the depletion of Skp[2] induces young EPCs to gain senescent phenotypes and reduces mitochondrial respiratory efficiency, we evaluated whether geriatric stress caused in vivo EPC bioenergetic profile changes
Summary
Advanced age is a strong and independent risk factor for the development of atherosclerosis-related diseases. Www.nature.com/scientificreports were infected with adenoviral vectors expressing Skp[2] or luciferase and subjected to analysis to evaluate SA-βGal activity, cell proliferation, and the bioenergetics profile. Skp[2] was depleted by siRNA, which resulted in a pronounced decrease in protein level (Fig. 2A) and a significant increase in SA-βGal activity in young EPCs (Fig. 2B and quantification).
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