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<p>Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by adverse effects. MiR-454-3p targets ET-1. This study aimed to investigate the role of miR-454-3p in modulating ET-1 expression and related molecular changes in endothelial cells (ECs) under high glucose conditions using both bioinformatics and experimental approaches. Bioinformatics analysis identified 10 miR-454-3p target genes expressed in ECs previously implicated in diabetic vascular complications: ET-1, GJA1, IRF1, PIK3CB, TRPC3, SLMAP, ESR1, ITGB8, MAPK1, and PPARG. With the exception of PPARG, which protects ECs from hyperglycemia-induced damage, all have been reported to exacerbate endothelial dysfunction. Western blotting showed that high glucose increased ET-1 expression in human umbilical vein ECs (HUVECs) and human dermal microvascular endothelial cells (HDMECs), while miR-454-3p overexpression significantly suppressed this effect in both cell types. Conditioned medium (CM) from HUVECs transfected with miR-454-3p mimics enhanced eNOS expression in recipient cells, compared to control CM. Pre-treatment of HUVEC control CM with an anti-ET-1 antibody also increased eNOS expression, supporting that miR-454-3p promotes NOS production partly via ET-1 suppression. MiR-454-3p overexpression in HUVECs did not affect PPARG expression or cell proliferation. In conclusion, miR-454-3p overexpression inhibits high glucose-induced ET-1 expression in HUVECs and HDMECs, and promotes eNOS production without affecting PPARG expression in HUVECs. Our findings suggest that miR-454-3p modulates ET-1 expression under hyperglycemic conditions in vitro, which may provide a foundation for future studies exploring its potential application in managing diabetic vasculopathy.</p>

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Overexpression of miR-454-3p inhibits high glucose-induced ET-1 expression, leading to eNOS upregulation in endothelial cells: an integrated bioinformatics and experimental analysis

  • 期刊论文

  • 发表日期：

    2025年10月26日

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  • Weifang Li,
  • Qiuwang Zhang,
  • Michael J. B. Kutryk

摘要

Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by adverse effects. MiR-454-3p targets ET-1. This study aimed to investigate the role of miR-454-3p in modulating ET-1 expression and related molecular changes in endothelial cells (ECs) under high glucose conditions using both bioinformatics and experimental approaches. Bioinformatics analysis identified 10 miR-454-3p target genes expressed in ECs previously implicated in diabetic vascular complications: ET-1, GJA1, IRF1, PIK3CB, TRPC3, SLMAP, ESR1, ITGB8, MAPK1, and PPARG. With the exception of PPARG, which protects ECs from hyperglycemia-induced damage, all have been reported to exacerbate endothelial dysfunction. Western blotting showed that high glucose increased ET-1 expression in human umbilical vein ECs (HUVECs) and human dermal microvascular endothelial cells (HDMECs), while miR-454-3p overexpression significantly suppressed this effect in both cell types. Conditioned medium (CM) from HUVECs transfected with miR-454-3p mimics enhanced eNOS expression in recipient cells, compared to control CM. Pre-treatment of HUVEC control CM with an anti-ET-1 antibody also increased eNOS expression, supporting that miR-454-3p promotes NOS production partly via ET-1 suppression. MiR-454-3p overexpression in HUVECs did not affect PPARG expression or cell proliferation. In conclusion, miR-454-3p overexpression inhibits high glucose-induced ET-1 expression in HUVECs and HDMECs, and promotes eNOS production without affecting PPARG expression in HUVECs. Our findings suggest that miR-454-3p modulates ET-1 expression under hyperglycemic conditions in vitro, which may provide a foundation for future studies exploring its potential application in managing diabetic vasculopathy.