Gastrodin attenuates diabetic cardiomyopathy characterized by myocardial fibrosis by inhibiting the KLK8-PAR1 signaling axis

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Abstract

Background

Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated.

Methods

In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS.

Results

GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling.

Conclusion

GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s13020-024-01035-4.

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Author and article information

Contributors

Ling Tao: tl15285581860@163.com

Min Zhang: 1071632869@qq.com

Xiangchun Shen:

ORCID: http://orcid.org/0000-0002-4333-9106

shenxiangchun@126.com

Journal

Journal ID (nlm-ta): Chin Med

Journal ID (iso-abbrev): Chin Med

Title: Chinese Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1749-8546

Publication date (Electronic): 22 November 2024

Publication date PMC-release: 22 November 2024

Publication date Collection: 2024

Volume: 19

Electronic Location Identifier: 164

Affiliations

[1 ]The State Key Laboratory of Functions and Applications of Medicinal Plants, The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, ( https://ror.org/035y7a716) No.6 Ankang Avenue, Guian New District, Guiyang, 561113 Guizhou China

[2 ]Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, ( https://ror.org/035y7a716) Guian New District, Guiyang , 561113 Guizhou China

[3 ]The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guian New District, Guiyang, 561113 Guizhou China

Author information

Xiangchun Shen http://orcid.org/0000-0002-4333-9106

Article

Publisher ID: 1035

DOI: 10.1186/s13020-024-01035-4

PMC ID: 11583739

PubMed ID: 39578836

SO-VID: 90878c89-6782-4f92-ba2f-10718c943506

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 July 2024

Date accepted : 7 November 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100014718, Innovative Research Group Project of the National Natural Science Foundation of China;

Award ID: No.82060729

Award ID: U1812403-4-4

Funded by: FundRef http://dx.doi.org/10.13039/501100004001, Guizhou Provincial Science and Technology Department;

Award ID: [2020]1Z069

Award ID: [2023]003

Funded by: FundRef http://dx.doi.org/10.13039/100015789, Dalian High-Level Talent Innovation Program;

Award ID: No. GCC [2023]048

Custom metadata

ScienceOpen disciplines: Complementary & Alternative medicine

Keywords: diabetic cardiomyopathy,myocardial fibrosis,gastrodin,klk8

Data availability: