Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury.
BACKGROUND
It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo.


RESULTS
Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury.


CONCLUSIONS
These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.
Shishido
Tetsuro
T
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Japan. Tetsuro_Shishido@URMC.Rochester.edu
Nozaki
Naoki
N
Takahashi
Hiroki
H
Arimoto
Takanori
T
Niizeki
Takeshi
T
Koyama
Yo
Y
Abe
Jun-Ichi
J
Takeishi
Yasuchika
Y
Kubota
Isao
I
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D016207:Cytokines / Q000235:genetics; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism*; D005786:Gene Expression Regulation; D006339:Heart Rate / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051195:Toll-Like Receptor 2