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)-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.