Published online Mar 15, 2023. doi: 10.4239/wjd.v14.i3.234
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
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. Tongxinluo (TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease.
To investigate the effect of TXL on diabetic PAD and its underlying mechanisms.
In the current study, it was shown that TXL promoted arteriogenesis in diabetic mice with HLI, which may be achieved by the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and enhancement of the interaction between endothelial cells and smooth muscle cells. This study provides an experimental basis for the clinical application of TXL in the treatment of diabetic PAD, which provides evidence and direction for further research in the future.
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 immunosorbent 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.
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 ROS/NLRP3/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.
TXL promoted arteriogenesis in diabetic mice with HLI, which may be achieved by the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and enhancement of the interaction between endothelial cells and smooth muscle cells.
Since there was no db/db sham group in this study, we were unable to determine whether diabetes or arterial ligation caused inflammation as well as endothelial injury. We believe that the increased inflammatory response in the hindlimb as well as the endothelial damage may be caused by the combination of diabetes and arterial ligation. We will demonstrate this further in a future study.