The REDD1–NF-κB–miRNAs–eNOS/SIRT1 axis mediates obesity-induced endothelial cell senescence and hypertension

Vascular dysfunction, including endothelial cell (EC) senescence and hypertension, is a hallmark of metabolic syndrome, yet its underlying mechanisms remain unclear. Here, we show that metabolic stress upregulates regulated in development and DNA damage response 1 (REDD1), driving vascular dysfunction. Overexpression of REDD1, but not the REDD1KK219/220AA mutant, which cannot activate atypical NF-κB, promotes EC senescence and hypertension through NF-κB-dependent induction of miR-155-5p and miR-214-3p. These miRNAs suppress endothelial nitric oxide synthase (eNOS) and SIRT1 expression in human and mouse ECs. In obese male mice, REDD1 and miR-214-3p are upregulated, whereas eNOS and SIRT1 are downregulated, contributing to EC senescence, renal dysfunction, and hypertension. This phenotype is alleviated in mice lacking Redd1, EC-specific Redd1, or miR-214-3p, and in mice expressing Redd1KK219/220AA, but only partially by IKKβ inhibition. These findings identify a REDD1–atypical NF-κB–miRNAs–eNOS/SIRT1 axis as a critical mediator of obesity-induced vascular dysfunction and a promising therapeutic target. This study found that obesity increases the stress protein REDD1, which drives vascular ageing and high blood pressure. REDD1 activates an atypical NF-κB signaling pathway and microRNAs that switch off genes protecting blood vessels. Blocking this pathway improves vascular and kidney function in obese mice, highlighting a potential therapeutic target.