Overexpression of the CDK5 regulatory subunit p25 in endothelial cells promotes endothelial senescence and adverse arterial remodeling in arteries

Abstract

Background- P25 is a 209-amino acid COOH-terminal fragment of the regulatory subunit 1 (p35) for CDK5, a proline-directed serine/threonine kinase. Upregulation of p25 triggers a sustained activation of CDK5 and hyperphosphorylation of various substrates including SIRT1, the longevity regulator, in endothelial cells (1). The present study investigated the role of endothelial p25 in regulating endothelial senescence and adverse arterial remodeling. Methods and Results- Overexpression of p25 in primary porcine aortic endothelial cells impaired cell proliferation and promoted senescence. Transgenic mice (EC-p25) with selective and controlled overexpression of p25 in vascular endothelial cells were generated. Compared to wild type littermates, arteries from 20-weeks old EC-p25 mice exhibited increased expression levels of various pro-inflammatory markers, such as TNFα, MCP1, TGF-β, P-selectin and MMP9. Under low-flow conditions, carotid arteries of EC-p25 mice showed significant neointima formation, as a result of hyperplasia and infiltration of vascular smooth muscle cells. The gene and protein expressions of soluble guanylyl cyclase (sGC) subunit β1 were significantly downregulated in arteries of EC-p25, possible via the regulation of endothelial SIRT1. Conclusion- The results implied a pathophysiological role of CDK5-p35/p25-SIRT1-sGC signaling axis in arterial remodeling and early vascular ageing will be discussed. Reference: 1. Bai B, Liang Y, Xu C, et al. CDK5-mediated hyperphosphorylation of SIRT1 contributes to the development of endothelial senescence and atherosclerosis[J]. Circulation, 2012: CIRCULATIONAHA. 112.118778.