Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2023; 14(3): 234-254
Published online Mar 15, 2023. doi: 10.4239/wjd.v14.i3.234
Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease
Jiao-Jiao Gu, Yun-Long Hou, Yi-Hui Yan, Jie Li, Ya-Ru Wei, Kun Ma, Xiao-Qi Wang, Jie-Han Zhang, Dan-Dong Wang, Cui-Ru Li, Dong-Qi Li, Ling-Ling Sun, Huai-Lin Gao
Jiao-Jiao Gu, Yun-Long Hou, Yi-Hui Yan, Jie Li, Ya-Ru Wei, Kun Ma, Xiao-Qi Wang, Dong-Qi Li, Huai-Lin Gao, Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050090, Hebei Province, China
Jie-Han Zhang, Dan-Dong Wang, Graduate School, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
Cui-Ru Li, Graduate school, Hebei Yiling Pharmaceutical Research Institute, Shijiazhuang 050035, Hebei Province, China
Ling-Ling Sun, Graduate school, Henan University of Traditional Chinese Medicine, Shijiazhuang 450000, Hebei Province, China
Author contributions: Gu JJ analyzed data and wrote the paper; Yan YH, Li J, Zhang JH and Wang DD performed research and tested indicators; Wei YR, Ma K and Wang XQ revised the paper; Li CR, Li DQ and Ling-Ling Sun analyzed data; Gao HL and Hou YL designed research.
Supported by The Hebei Province Natural Science Foundation, No. H2019106062; Key R&D Plan of Hebei Provincial Department of Science and Technology, No. 223777155D; and Research Project of Hebei Provincial Administration of Traditional Chinese Medicine, No. 2023179.
Institutional review board statement: All experimental protocols and animal treatment procedures were reviewed and approved by the Animal Ethics Committee of Hebei Yiling Pharmaceutical Co., Ltd. (No. N2021-060).
Institutional animal care and use committee statement: All experimental protocols and animal treatment procedures were reviewed and approved by the Animal Ethics Committee of Hebei Yiling Pharmaceutical Co., Ltd. (No. N2021-060).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Huai-Lin Gao, PhD, Doctor, Professor, Graduate School, Hebei University of Chinese Medicine, No. 326 Xinshinan 11 Road, Qiaoxi District, Shijiazhuang 050090, Hebei Province, China. gaohuailin@126.com
Received: November 21, 2022
Peer-review started: November 21, 2022
First decision: January 5, 2023
Revised: January 12, 2023
Accepted: February 27, 2023
Article in press: February 27, 2023
Published online: March 15, 2023
Processing time: 114 Days and 12.6 Hours
Abstract
BACKGROUND

Peripheral arterial disease (PAD) has become one of the leading causes of disa-bility and death in diabetic patients. Restoring blood supply to the hindlimbs, especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. Tongxinluo (TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease.

AIM

To investigate the effect of TXL on diabetic PAD and its underlying mechanisms.

METHODS

An animal model of diabetic PAD was established by ligating the femoral artery of db/db mice. Laser Doppler imaging and micro-computed tomography (micro-CT) were performed to assess the recovery of blood flow and arteriogenesis. Endothelial cell function related to arteriogenesis and cellular pyroptosis was assessed using histopathology, Western blot analysis, enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction assays. In vitro, human vascular endothelial cells (HUVECs) and human vascular smooth muscle cells (VSMCs) were pretreated with TXL for 4 h, followed by incubation in high glucose and hypoxia conditions to induce cell injury. Then, indicators of HUVEC pyroptosis and function, HUVEC-VSMC interactions and the migration of VSMCs were measured.

RESULTS

Laser Doppler imaging and micro-CT showed that TXL restored blood flow to the hindlimbs and enhanced arteriogenesis. TXL also inhibited endothelial cell pyroptosis via the reactive oxygen species/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3/Caspase-1/GSDMD signaling pathway. In addition, TXL restored endothelial cell functions, including maintaining the balance of vasodilation, acting as a barrier to reduce inflammation, and enhancing endothelial-smooth muscle cell interactions through the Jagged-1/Notch-1/ephrin-B2 signaling pathway. Similar results were observed in vitro.

CONCLUSION

TXL has a pro-arteriogenic effect in the treatment of diabetic PAD, and the mechanism may be related to the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and promotion of endothelial cell-smooth muscle cell interactions.

Keywords: Diabetic peripheral arterial disease, Arteriogenesis, Endothelial cell, Inflammation, Pyroptosis

Core Tip: Peripheral arterial disease (PAD) has become one of the leading causes of disability and death in diabetic patients. Restoring blood supply to the hindlimbs, especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. The present study demonstrated the role of Tongxinluo in promoting arteriogenesis in the treatment of diabetic PAD, and the mechanism may be related to the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function, and promotion of endothelial-smooth muscle cell interaction.