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

doi:10.4239/wjd.v14.i3.234

Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease

World J Diabetes. 2023 Mar 15;14(3):234-254. doi: 10.4239/wjd.v14.i3.234.

Authors

Jiao-Jiao Gu¹, Yun-Long Hou¹, Yi-Hui Yan¹, Jie Li¹, Ya-Ru Wei¹, Kun Ma¹, Xiao-Qi Wang¹, Jie-Han Zhang², Dan-Dong Wang², Cui-Ru Li³, Dong-Qi Li¹, Ling-Ling Sun⁴, Huai-Lin Gao⁵

Affiliations

¹ Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050090, Hebei Province, China.
² Graduate School, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China.
³ Graduate school, Hebei Yiling Pharmaceutical Research Institute, Shijiazhuang 050035, Hebei Province, China.
⁴ Graduate school, Henan University of Traditional Chinese Medicine, Shijiazhuang 450000, Hebei Province, China.
⁵ Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050090, Hebei Province, China. gaohuailin@126.com.

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: Arteriogenesis; Diabetic peripheral arterial disease; Endothelial cell; Inflammation; Pyroptosis.