SP600125 Attenuates Nicotine-Related Aortic Aneurysm Formation by Inhibiting Matrix Metalloproteinase Production and CC Chemokine-Mediated Macrophage Migration.
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.
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Zhen-Zhen
0000-0002-1721-908X
ZZ
Guo
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Qun-An
0000-0003-3329-4167
QA
Cao
Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang 550002, China.
Zong-Zhuang
0000-0002-2109-9295
ZZ
Li
Department of Cardiology, Yancheng First People's Hospital, The Fourth Affiliated Hospital of Nantong Medical University, Jiangsu 224001, China.
Li-Ping
LP
Liu
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Zhi
0000-0002-0253-8192
Z
Zhang
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Ya-Juan
YJ
Zhu
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Guang
G
Chu
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Qiu-Yan
0000-0002-9707-5281
QY
Dai
J Mol Cell Cardiol. 2015 Oct;87:160-70
26299839
Sci Transl Med. 2012 Feb 22;4(122):122ra22
22357537
Cardiovasc Res. 2012 Dec 1;96(3):543-51
22871590
Springerplus. 2015 May 16;4:231
26110102
Mediators Inflamm. 2015;2015:896283
25922566
J Appl Physiol (1985). 1998 Jun;84(6):2089-98
9609804
Mol Cell Biochem. 2015 Jan;399(1-2):49-58
25381636
Sci Rep. 2015 Oct 28;5:15730
26508670
Vasc Health Risk Manag. 2008;4(5):1095-102
19183758
J Vasc Surg. 2003 Jul;38(1):138-46
12844103
Mol Cell Biochem. 2015 Dec;410(1-2):75-84
26318311
Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):670-2
23486768
Nat Med. 2012 Jun 06;18(6):856-8
22673993
J Surg Res. 2014 Jul;190(1):328-34
24726061
Circulation. 2001 Jul 17;104(3):304-9
11457749
Mediators Inflamm. 2012;2012:103120
22529515
Nat Med. 2005 Dec;11(12 ):1330-8
16311603
J Clin Invest. 2008 Sep;118(9):3012-24
18677407
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2605-13
16973970
J Am Heart Assoc. 2014 May 08;3(3):e000747
24811612
PLoS One. 2015 Feb 23;10(2):e0118344
25706869
Nat Med. 2012 Jun;18(6):902-10
22561688
Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):e52-6
26490276
Vascul Pharmacol. 2015 Oct;73:86-95
25912763