AGEs inhibit scavenger receptor class B type I gene expression via Smad1 in HUVECs

Hiromi Nagata, Jingya Lyu, Hitomi Imachi, Kensaku Fukunaga, Seisuke Sato, Toshihiro Kobayashi, Takanobu Saheki, Kayoko Seo, Japar B. Salimah, Hisakazu Iwama, Ryuichi Sakamoto, Yoshihiro Ogawa, Koji Murao

研究成果: Contribution to journalArticle査読

抄録

Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.

本文言語英語
ページ(範囲)223-231
ページ数9
ジャーナルJournal of Molecular Endocrinology
66
3
DOI
出版ステータス出版済み - 3 1 2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 内分泌学

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