Treponema pallidum membrane protein Tp47 promotes angiogenesis through ROS-induced autophagy
Wei Li1, Lin Xie1, Qiu-Ling Li1
1Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Background:
Pathological angiogenesis is an important manifestation of syphilis, but the underlying mechanism of Treponema pallidum subspecies pallidum (T. pallidum)-induced angiogenesis is poorly understood.
Objectives:
The objective of this study is to investigate the role and related mechanism of the T. pallidum membrane protein Tp47 in angiogenesis.
Methods:
The proangiogenic activity of recombinant T. pallidum membrane protein Tp47 in human umbilical vein endothelial cells (HUVECs) was assessed by tube formation assay, three-dimensional angiogenesis analysis and experiments with a zebrafish embryo model. The effects of mitochondrial ROS and NADPH oxidase on intracellular ROS induced by Tp47 were further investigated. Furthermore, the levels of autophagy-related proteins and autophagic flux were measured. Finally, the role of ROS-induced autophagy in angiogenesis was studied.
Results:
Tp47 promoted tubule formation and the formation of angiogenic sprouts in vitro. In addition, a significant increase in the number of subintestinal vessel branch points in zebrafish injected with Tp47 was observed using a zebrafish embryo model. Tp47 also significantly increased intracellular ROS levels in a dose-dependent manner. Tp47-induced tube formation and angiogenic sprout formation were effectively prevented by the ROS inhibitor NAC. In addition, Tp47 enhanced the production of mitochondrial ROS and expression of the NADPH oxidase-related proteins Nox2 and Nox4. The production of mitochondrial ROS and intracellular ROS was reduced by the NADPH oxidase inhibitors DPI and apocynin. Furthermore, Tp47 significantly increased expression of the autophagy-related proteins P62 and Beclin 1 and the LC3-II/LC3-I ratio and promoted an increase in autophagic flux, which could be effectively rescued by coincubation with the ROS inhibitor NAC. Further intervention with the autophagy inhibitor BafA1 significantly inhibited tube formation and angiogenic sprout formation.
Conclusions:
Tp47-induced NADPH oxidase enhanced intracellular ROS production via mitochondrial ROS and promoted angiogenesis through autophagy mediated by ROS. These findings may contribute to our understanding of pathological angiogenesis in syphilis.
Insights
The Treponema pallidum membrane protein Tp47 promotes pathological angiogenesis by increasing reactive oxygen species (ROS) via NADPH oxidase and mitochondrial ROS, which activates autophagy. This mechanism drives new blood vessel formation in syphilis.
Area of Science:
- Vascular Biology
- Microbiology
- Cellular Mechanisms
Background:
- Pathological angiogenesis is a key feature of syphilis.
- The precise mechanisms of *Treponema pallidum* ( *T. pallidum* )-induced angiogenesis remain unclear.
Purpose of the Study:
- To investigate the role of the *T. pallidum* membrane protein Tp47 in angiogenesis.
- To elucidate the underlying molecular mechanisms of Tp47-induced angiogenesis.
Main Methods:
- Assessed proangiogenic activity of Tp47 using *in vitro* tube formation assays and a zebrafish embryo model.
- Investigated the role of mitochondrial reactive oxygen species (ROS) and NADPH oxidase in Tp47-induced ROS production.
- Measured autophagy-related proteins and autophagic flux to determine the involvement of autophagy.
Main Results:
- Tp47 significantly promoted angiogenesis *in vitro* and *in vivo*.
- Tp47 increased intracellular ROS levels, mediated by mitochondrial ROS and NADPH oxidase (Nox2, Nox4).
- ROS-induced autophagy, evidenced by increased P62, Beclin 1, LC3-II/LC3-I ratio, and autophagic flux, was crucial for Tp47-driven angiogenesis.
Conclusions:
- *T. pallidum* Tp47 induces angiogenesis via NADPH oxidase-mediated ROS production and subsequent ROS-dependent autophagy.
- Understanding this pathway offers insights into the pathological angiogenesis associated with syphilis.
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