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<p>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 <Emphasis Type="Underline">re</Emphasis>gulated in <Emphasis Type="Underline">d</Emphasis>evelopment and <Emphasis Type="Underline">D</Emphasis>NA 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 <i>Redd1</i>, EC-specific <i>Redd1</i>, or miR-214-3p, and in mice expressing <i>Redd1</i><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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Yoon Kyung Choi,
  • Dong-Keon Lee,
  • Minsik Park,
  • Junyoung Byeon,
  • Woo-Young Nam,
  • Thuy Linh Lai,
  • Kyu Nam Kim,
  • Okhwa Kim,
  • Sungwoo Ryoo,
  • Jeong-Hyung Lee,
  • Young-Guen Kwon,
  • Ji-Yoon Kim,
  • Young-Myeong Kim

摘要

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.