NOLC1 as Key Regulator of NPR1 (Coding for NPRA) Transcription in Endothelial Senescence

Abstract

Vascular endothelial cell senescence is closely associated with cardiovascular disease. The deficiency of natriuretic peptide receptor A (NPRA), encoded by the natriuretic peptide receptor 1 (NPR1) gene, contributes to vascular endothelial aging, but the cause of its reduced expression is unclear. In this study, we performed reverse chromatin immunoprecipitation (R-ChIP) to analyze the binding proteins of the NPR1 promoter and found that nucleolar and coiled body phosphoprotein 1 (NOLC1) functions as a key regulator of NPRA transcription in endothelial cells. Similar to NPRA, NOLC1 is also expressed at reduced levels in senescent endothelial cells. Knockdown of NOLC1 decreased both NPRA mRNA and protein expression levels. Furthermore, inhibition of NOLC1 expression triggered cellular senescence hallmarks, including elevated p53/p21 levels, enhanced SA-β-gal activity, ROS accumulation, G0/G1 cell cycle arrest, and impaired migration. NPRA overexpression rescued senescence and dysfunction in NOLC1-deficient cells, restoring proliferative and migratory capacity. In conclusion, our findings demonstrate that nucleolar phosphoprotein NOLC1 is a key regulator of NPRA transcription in endothelial senescence.