The REDD1-NF-κB-miRNAs-eNOS/SIRT1 axis mediates obesity-induced endothelial cell senescence and hypertension.
basic_science · Level V
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- Record sourced from PubMed, PMID 41820389.
- Also identified by DOI 10.1038/s41467-026-70601-1.
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Abstract
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 REDD1<sup>KK219/220AA</sup> 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 Redd1<sup>KK219/220AA</sup>, 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.