Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice.
BACKGROUND
Inflammatory cytokines such as interleukin (IL)-1 beta 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-1 beta 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.


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-1 beta 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.
Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Noriyuki
N
Yajima
Masafumi
M
Takahashi
Hajime
H
Morimoto
Yuji
Y
Shiba
Yasuko
Y
Takahashi
Junya
J
Masumoto
Hirohiko
H
Ise
Junji
J
Sagara
Jun
J
Nakayama
Shun'ichiro
S
Taniguchi
Uichi
U
Ikeda
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D016026:Bone Marrow Transplantation; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology*; D014652:Vascular Diseases / Q000473:pathology* / Q000503:physiopathology*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C498534:Pycard protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases