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SP600125 Attenuates Nicotine-Related Aortic Aneurysm Formation by Inhibiting Matrix Metalloproteinase Production and
Zhen-Zhen Guo1, Qun-An Cao1, Zong-Zhuang Li2
1Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Abstract:
Nicotine, a major chemical component of cigarettes, plays a pivotal role in the development of abdominal aortic aneurysm (AAA). c-Jun N-terminal kinase (JNK) has been demonstrated to participate in elastase-induced AAA. This study aimed to elucidate whether the JNK inhibitor SP600125 can attenuate nicotine plus angiotensin II- (AngII-) induced AAA formation and to assess the underlying molecular mechanisms. SP600125 significantly attenuated nicotine plus AngII-induced AAA formation. The expression of matrix metalloproteinase- (MMP-) 2, MMP-9, monocyte chemoattractant protein- (MCP-) 1, and regulated-on-activation, normal T-cells expressed and secreted (RANTES) was significantly upregulated in aortic aneurysm lesions but inhibited by SP600125. In vitro, nicotine induced the expression of MCP-1 and RANTES in both RAW264.7 (mouse macrophage) and MOVAS (mouse vascular smooth muscle) cells in a dose-dependent manner; expression was upregulated by 0.5 ng/mL nicotine but strongly downregulated by 500 ng/mL nicotine. SP600125 attenuated the upregulation of MCP-1 and RANTES expression and subsequent macrophage migration. In conclusion, SP600125 attenuates nicotine plus AngII-induced AAA formation likely by inhibiting MMP-2, MMP-9, MCP-1, and RANTES. The expression of chemokines in MOVAS cells induced by nicotine has an effect on RAW264.7 migration, which is likely to contribute to the development of nicotine-related AAA.
Insights
The JNK inhibitor SP600125 reduces abdominal aortic aneurysm (AAA) formation caused by nicotine and angiotensin II. It works by decreasing inflammatory markers like MMP-2, MMP-9, MCP-1, and RANTES, crucial in AAA development.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Nicotine in cigarettes is a key factor in abdominal aortic aneurysm (AAA) development.
- c-Jun N-terminal kinase (JNK) signaling is implicated in elastase-induced AAA.
- The role of JNK in nicotine-induced AAA requires further elucidation.
Purpose of the Study:
- To investigate if the JNK inhibitor SP600125 can prevent AAA formation induced by nicotine and angiotensin II (AngII).
- To explore the molecular mechanisms underlying SP600125's potential protective effects against AAA.
Main Methods:
- Administered nicotine plus AngII to induce AAA in a model system.
- Treated with the JNK inhibitor SP600125.
- Assessed AAA formation, expression of matrix metalloproteinases (MMP-2, MMP-9), and chemokines (MCP-1, RANTES) in aortic tissue.
- Conducted in vitro studies using RAW264.7 (macrophage) and MOVAS (vascular smooth muscle) cells to examine chemokine expression and macrophage migration.
Main Results:
- SP600125 significantly attenuated nicotine plus AngII-induced AAA formation.
- Expression of MMP-2, MMP-9, MCP-1, and RANTES was upregulated in AAA lesions but reduced by SP600125.
- Nicotine induced MCP-1 and RANTES expression in a dose-dependent manner in both cell types.
- SP600125 inhibited nicotine-induced chemokine expression and subsequent macrophage migration.
Conclusions:
- SP600125 effectively attenuates nicotine plus AngII-induced AAA formation.
- The protective mechanism involves the inhibition of MMP-2, MMP-9, MCP-1, and RANTES.
- Nicotine-induced chemokine expression in vascular smooth muscle cells influences macrophage migration, contributing to AAA development.
