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Ginkgolide B caused the activation of the Akt/eNOS pathway through the antioxidant effect of SOD1 in the diabetic aorta

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Abstract

Ginkgo biloba extract (GBE) helps lower cardiovascular disease risk. Diabetes mellitus (DM)-induced endothelial dysfunction is a critical and initiating factor in the beginning of diabetic vascular complications. It was reported that GBE causes an endothelial-dependent relaxation. This study was designed to figure out the molecular basis on which GBE protects from endothelial dysfunction in diabetes because the underlying mechanisms are unclear. Studies were performed in a normal control group and streptozotocin/nicotinamide-induced DM group. In aortas, notably diabetic aortas, GBE, and ginkgolide B (GB), a constituent of GBE, produced a dose-dependent relaxation. The relaxation by GB was abolished by prior incubation with L-NNA (an endothelial nitric oxide synthase (NOS) inhibitor), LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor), and Akt inhibitor, confirming the essential role of PI3K/Akt/eNOS signaling pathway. We also demonstrated that GB induced the phosphorylation of Akt and eNOS in aortas. The superoxide dismutase1 (SOD1) expression level decreased in DM aortas, but GB stimulation increased SOD activity and SOD1 expression in DM aortas. Our novel findings suggest that in DM aortas, endothelial-dependent relaxation induced by GB was mediated by activation of SOD1, resulting in activation of the Akt/eNOS signaling pathway.

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Acknowledgements

We thank I. Tano and N. Bessho for technical assistance. We thank Enago (www.Enago.jp) for the English language review.

Funding

This work was partly supported by the JSPS KAKENHI Grant Numbers JP21K06811 (to Kumiko Taguchi) and JP21K06878 (to Tsuneo Kobayashi).

Japan Society for the Promotion of Science,JP21K06811,JP21K06878

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Authors and Affiliations

  1. Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501, Japan

    Kumiko Taguchi, Kanami Okudaira, Takayuki Matsumoto & Tsuneo Kobayashi

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  1. Kumiko Taguchi
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  2. Kanami Okudaira
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  3. Takayuki Matsumoto
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  4. Tsuneo Kobayashi
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Contributions

Kumiko Taguchi conceived and designed the study, performed the statistical analysis, and wrote the manuscript. Kumiko Taguchi and Kanami Okudaira conducted the experiments. Takayuki Matsumoto and Tsuneo Kobayashi helped develop the project, perform some experiments, and write the manuscript. Tsuneo Kobayashi is the guarantor of this work and approved the final version of the manuscript.

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Correspondence to Tsuneo Kobayashi.

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The animal study was reviewed and approved by the Hoshi University Animal Care and Use Committee. The application of approval number is P22-003. Consent to participate is “not applicable” as human study is not included in this work.

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Human ethics is “not applicable” as human study is not included in this work. This study was performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals from the Committee for the Care and Use of Laboratory Animals of Hoshi University (Tokyo, Japan).

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Taguchi, K., Okudaira, K., Matsumoto, T. et al. Ginkgolide B caused the activation of the Akt/eNOS pathway through the antioxidant effect of SOD1 in the diabetic aorta. Pflugers Arch - Eur J Physiol 475, 453–463 (2023). https://doi.org/10.1007/s00424-023-02790-3

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