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The SGLT2 Inhibitor Canagliflozin Reduces Atherosclerosis by Enhancing Macrophage Autophagy

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Abstract

It has been shown that SGLT2 suppresses atherosclerosis (AS). Recent studies indicate that autophagy widely participates in atherogenesis. This study aimed to assess the effect of canagliflozin (CAN) on atherogenesis via autophagy. Macrophages and ApoE − / − mice were used in this study. In macrophages, the results showed that CAN promoted LC3II expression and autophagosome formation. Furthermore, the cholesterol efflux assay demonstrated that CAN enhanced cholesterol efflux from macrophages via autophagy, resulting in lower lipid droplet concentrations in macrophages. The western blot revealed that CAN regulated autophagy via the AMPK/ULK1/Beclin1 signaling pathway. CAN resulted in increased macrophage autophagy in atherosclerotic plaques of ApoE − / − mice, confirming that CAN could inhibit the progression of AS via promoting macrophage autophagy. The current study found that CAN reduced the production of atherosclerotic lesions, which adds to our understanding of how SGLT2 inhibitors function to delay the progression of AS.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

CAD:

Coronary artery disease

AS:

Atherosclerosis

SGLT2:

Sodium-Glucose Co-Transporter 2

ApoE:

Apolipoprotein E

ApoE − / − :

Apolipoprotein E deficient

HFD:

High-fat diet

ox-LDL:

Oxidized low-density lipoprotein

AMPK:

Adenosine 5′-monophosphate-activated protein kinase

ULK1:

UNC-51-like autophagy-activating kinase 1

ATG:

Autophagy-related gene

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Acknowledgements

We thank Jiahui Wang, Peng Zhu, and Huishan Zhao (Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University) for their technical assistance.

Funding

Key Research and Development Program of Shandong Province (No. 2019GSF108142), Natural Science Foundation of Shandong Province (No. ZR2022MH151), National Natural Science Foundation of China (No. 81900310) (No. 82200503), Science and Technology Program of Yantai City (No. 2021MSGY042 and), Science and Technology Program of Yantai City (No. 2021MSGY044), and Youth Research Foundation of Yuhuangding Hospital (No. 2021–03).

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration. Informed consent was obtained from all patients before being included in the study. The human research protocol was approved by the medical ethics committee of Yantai Yuhuangding Hospital, affiliated with Qingdao University (NO.2021–346). All Institutional and National Guidelines for the care and use of animals (fisheries) were followed. The animal research was approved by the Institutional Animal Care and Use Committee at Qingdao University (NO.QDU-AEC-2021176).

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Author notes

  1. Hongping Chen and Da Teng contributed equally to this work.

Authors and Affiliations

  1. School of Medicine, Qingdao University, Qingdao, China

    Hongping Chen & Da Teng

  2. Department of Cardiology, Yuhuangding Hospital, The Fourth School of Clinical Medicine of Qingdao University, Yantai, Shandong Province, China

    Hongping Chen, Da Teng, Chunxiao Wang, Hua Wang, Wenjuan Jia, Lei Gong, Haibin Dong, Lin Zhong & Jun Yang

  3. Binzhou Medical University, Yantai, Shandong Province, China

    Bowen Xu

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Correspondence to Lin Zhong or Jun Yang.

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Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration. Informed consent was obtained from all patients before being included in the study. The human research protocol was approved by the medical ethics committee of Yantai Yuhuangding Hospital, affiliated with Qingdao University (NO.2021-346). All Institutional and National Guidelines for the care and use of animals (fisheries) were followed. The animal research was approved by the Institutional Animal Care and Use Committee at Qingdao University (NO.QDU-AEC-2021176).

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Associate Editor Guoping Li oversaw the review of this article.

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Chen, H., Teng, D., Xu, B. et al. The SGLT2 Inhibitor Canagliflozin Reduces Atherosclerosis by Enhancing Macrophage Autophagy. J. of Cardiovasc. Trans. Res. 16, 999–1009 (2023). https://doi.org/10.1007/s12265-023-10390-w

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