TY - JOUR
T1 - Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice
AU - Yajima, Noriyuki
AU - Takahashi, Masafumi
AU - Morimoto, Hajime
AU - Shiba, Yuji
AU - Takahashi, Yasuko
AU - Masumoto, Junya
AU - Ise, Hirohiko
AU - Sagara, Junji
AU - Nakayama, Jun
AU - Taniguchi, Shun'ichiro
AU - Ikeda, Uichi
PY - 2008/6/17
Y1 - 2008/6/17
N2 - Background - Inflammatory cytokines such as interleukin (IL)-1β and IL-18 play an important role in the development of atherosclerosis and restenosis. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that regulates caspase-1-dependent IL-1β and IL-18 generation; however, the role of ASC in vascular injury remains undefined. Here, we investigated the contribution of ASC to neointimal formation after vascular injury in ASC-deficient (ASC -/-) mice. Methods and Results - Wire-mediated vascular injury was produced in the femoral artery of ASC -/- and wild-type mice. Immunohistochemical analysis revealed that ASC was markedly expressed at the site of vascular injury. Neointimal formation was significantly attenuated in ASC -/- mice after injury. IL-1β and IL-18 were expressed in the neointimal lesion in wild-type mice but showed decreased expression in the lesion of ASC -/- mice. To investigate the contribution of bone marrow-derived cells, we developed bone marrow-transplanted mice and found that neointimal formation was significantly decreased in wild-type mice in which bone marrow was replaced with ASC -/- bone marrow cells. Furthermore, in vitro experiments showed that the proliferation activity of ASC -/- vascular smooth muscle cells was not impaired. Conclusions - These findings suggest that bone marrow-derived ASC is critical for neointimal formation after vascular injury and identify ASC as a novel therapeutic target for atherosclerosis and restenosis.
AB - Background - Inflammatory cytokines such as interleukin (IL)-1β and IL-18 play an important role in the development of atherosclerosis and restenosis. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that regulates caspase-1-dependent IL-1β and IL-18 generation; however, the role of ASC in vascular injury remains undefined. Here, we investigated the contribution of ASC to neointimal formation after vascular injury in ASC-deficient (ASC -/-) mice. Methods and Results - Wire-mediated vascular injury was produced in the femoral artery of ASC -/- and wild-type mice. Immunohistochemical analysis revealed that ASC was markedly expressed at the site of vascular injury. Neointimal formation was significantly attenuated in ASC -/- mice after injury. IL-1β and IL-18 were expressed in the neointimal lesion in wild-type mice but showed decreased expression in the lesion of ASC -/- mice. To investigate the contribution of bone marrow-derived cells, we developed bone marrow-transplanted mice and found that neointimal formation was significantly decreased in wild-type mice in which bone marrow was replaced with ASC -/- bone marrow cells. Furthermore, in vitro experiments showed that the proliferation activity of ASC -/- vascular smooth muscle cells was not impaired. Conclusions - These findings suggest that bone marrow-derived ASC is critical for neointimal formation after vascular injury and identify ASC as a novel therapeutic target for atherosclerosis and restenosis.
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U2 - 10.1161/CIRCULATIONAHA.107.746453
DO - 10.1161/CIRCULATIONAHA.107.746453
M3 - Article
C2 - 18541743
AN - SCOPUS:48249134451
VL - 117
SP - 3079
EP - 3087
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 24
ER -