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Published on: May 14, 2013
TIPE2 protein prevents injury-induced restenosis in mice
Guizhong Zhang1, Lianying Zhao2, Yiyao Wang1
1Department of Immunology, Shandong University School of Medicine, Ji'nan, PR China.
Abstract:
Proliferation of vascular smooth muscle cells (VSMCs) plays an important role in restenosis, a disease characterized by smooth muscle cell hyperplasia and neointimal formation. How proliferation signals are controlled to avoid restenosis is not fully understood. Here we report that TIPE2, the tumor necrosis factor (TNF) α-induced protein 8-like 2 (TNFAIP8L2), suppresses injury-induced restenosis by inhibiting VSMCs proliferation. TIPE2 was significantly upregulated in VSMCs in response to PDGF-BB stimuli and injury. Enforced TIPE2 expression significantly suppressed VSMCs proliferation and cell cycle progression, whereas TIPE2 deficiency in VSMCs promoted cell proliferation and upregulated the expression of Cyclins D1 and D3. TIPE2 likely regulated VSMC proliferation via Rac1-STAT3 and ERK1/2 signaling pathways. It blocked STAT3 activation and nuclear translocation in a Rac1-dependent manner. As a result, TIPE2-deficient VSMCs exhibited enhanced proliferation whereas TIPE2-deficient mice developed more severe restenosis in response to vascular injury. Conversely, adenovirus-mediated gene transfer of TIPE2 significantly reduced injury-induced restenosis in mice. These results indicate that TIPE2 plays a suppressive role in injury-induced restenosis and may serve as a new therapeutic target for treating the disease.
Insights
Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) inhibits vascular smooth muscle cell proliferation, suppressing restenosis after injury. TIPE2 deficiency worsens restenosis, highlighting its therapeutic potential.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Signaling
Background:
- Vascular smooth muscle cell (VSMC) proliferation is a key driver of restenosis.
- Understanding the molecular mechanisms controlling VSMC proliferation is crucial for preventing this condition.
Purpose of the Study:
- To investigate the role of TIPE2 (TNFAIP8L2) in regulating VSMC proliferation and restenosis.
- To elucidate the signaling pathways involved in TIPE2-mediated suppression of VSMC growth.
Main Methods:
- Assessed TIPE2 expression in VSMCs following PDGF-BB stimulation and vascular injury.
- Utilized enforced TIPE2 expression and TIPE2 deficiency models in VSMCs and mice.
- Analyzed cell cycle progression, cyclin expression, and signaling pathways (Rac1-STAT3, ERK1/2).
- Employed adenovirus-mediated gene transfer to deliver TIPE2 in vivo.
Main Results:
- TIPE2 expression was upregulated in response to PDGF-BB and injury.
- Enforced TIPE2 expression suppressed VSMC proliferation and cell cycle progression.
- TIPE2 deficiency promoted VSMC proliferation and increased Cyclin D1/D3 levels.
- TIPE2 inhibited STAT3 activation and nuclear translocation via a Rac1-dependent mechanism.
- TIPE2 deficiency exacerbated injury-induced restenosis in mice, while TIPE2 gene transfer reduced it.
Conclusions:
- TIPE2 suppresses injury-induced VSMC proliferation and restenosis.
- TIPE2 acts through Rac1-STAT3 and ERK1/2 signaling pathways.
- TIPE2 represents a potential therapeutic target for preventing restenosis.
