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Objective <p>To determine whether berberine (BBR) attenuates angiotensin II (Ang II)-induced endothelial dysfunction by antagonizing AT1R and modulating the phosphodiesterase 4b (PDE4b)-related signaling pathway.</p> Methods <p>Primary aortic endothelial cells were isolated and cultured from control and Ang II-induced hypertensive mice. Human umbilical vein endothelial cells (HUVECs), mouse aortic endothelial cells (MAECs) and <i>ex vivo</i> mouse aortae were treated with Ang II (1 µ mol/L), in the presence or absence of BBR, or the PDE4b inhibitor piclamilast. Quantitative real-time PCR (qPCR), Western blot, immunofluorescence, and microplate assays were employed to assess mRNA and protein expressions of PDE4b, Ang II type 1 receptor (AT1R), endothelial nitric oxide synthase (eNOS) and protein kinase B (PKB, as known as Akt) phosphorylation, and intra- and extracellular nitric oxide (NO) levels. Vascular ring assays were conducted to evaluate the endothelium-dependent relaxation (EDR) of isolated mouse aortae. In addition, molecular docking and cellular thermal shift assays were performed to investigate the interaction between BBR and the AT1R, with comparison to valsartan.</p> Results <p>Ang II reduced eNOS phosphorylation and NO levels in HUVECs and impaired EDR in isolated mouse aortae (<i>P</i>&lt;0.01), which were reversed by BBR co-treatment (<i>P</i>&lt;0.05). BBR showed a binding free energy of −8.6 kCal/mol with AT1R and significantly enhanced AT1R thermal stability in 60, 65, 75 °C, exhibiting similar effects as valsartan in 60, 65, 75 °C (all <i>P</i>&lt;0.05). Ang II upregulated PDE4b mRNA and protein levels in HUVECs and MAECs, while BBR reversed this effect in HUVECs (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01). Ang II also suppressed Akt phosphorylation in HUVECs, which was restored by BBR, like the effect of piclamilast <i>(P</i>&lt;0.05 or <i>P</i>&lt;0.01).</p> Conclusions <p>BBR ameliorates Ang II-induced endothelial dysfunction primarily by antagonizing AT1R, suppressing PDE4b expression and restoring Akt/eNOS signaling. These findings provide mechanistic insights into BBR’s endothelial-protective actions and highlight its therapeutic potential in treating hypertension-related vascular complications.</p>

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Berberine Ameliorates Angiotensin II-Induced Endothelial Dysfunction by Blocking AT1R, Inhibiting PDE4b and Activating AKT/eNOS Pathway

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Ting-yue Zhang,
  • Bi-ning Zhao,
  • Hao-wen Wu,
  • You-you Zhang,
  • Jiang Li,
  • Qi-ming Liu,
  • Li-mei Liu,
  • Ji-hong Kang

摘要

Objective

To determine whether berberine (BBR) attenuates angiotensin II (Ang II)-induced endothelial dysfunction by antagonizing AT1R and modulating the phosphodiesterase 4b (PDE4b)-related signaling pathway.

Methods

Primary aortic endothelial cells were isolated and cultured from control and Ang II-induced hypertensive mice. Human umbilical vein endothelial cells (HUVECs), mouse aortic endothelial cells (MAECs) and ex vivo mouse aortae were treated with Ang II (1 µ mol/L), in the presence or absence of BBR, or the PDE4b inhibitor piclamilast. Quantitative real-time PCR (qPCR), Western blot, immunofluorescence, and microplate assays were employed to assess mRNA and protein expressions of PDE4b, Ang II type 1 receptor (AT1R), endothelial nitric oxide synthase (eNOS) and protein kinase B (PKB, as known as Akt) phosphorylation, and intra- and extracellular nitric oxide (NO) levels. Vascular ring assays were conducted to evaluate the endothelium-dependent relaxation (EDR) of isolated mouse aortae. In addition, molecular docking and cellular thermal shift assays were performed to investigate the interaction between BBR and the AT1R, with comparison to valsartan.

Results

Ang II reduced eNOS phosphorylation and NO levels in HUVECs and impaired EDR in isolated mouse aortae (P<0.01), which were reversed by BBR co-treatment (P<0.05). BBR showed a binding free energy of −8.6 kCal/mol with AT1R and significantly enhanced AT1R thermal stability in 60, 65, 75 °C, exhibiting similar effects as valsartan in 60, 65, 75 °C (all P<0.05). Ang II upregulated PDE4b mRNA and protein levels in HUVECs and MAECs, while BBR reversed this effect in HUVECs (P<0.05 or P<0.01). Ang II also suppressed Akt phosphorylation in HUVECs, which was restored by BBR, like the effect of piclamilast (P<0.05 or P<0.01).

Conclusions

BBR ameliorates Ang II-induced endothelial dysfunction primarily by antagonizing AT1R, suppressing PDE4b expression and restoring Akt/eNOS signaling. These findings provide mechanistic insights into BBR’s endothelial-protective actions and highlight its therapeutic potential in treating hypertension-related vascular complications.