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(Circulation. 2008;117:3079-3087.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice

Noriyuki Yajima, MD^*; Masafumi Takahashi, MD, PhD^*; Hajime Morimoto, DVM; Yuji Shiba, MD, PhD; Yasuko Takahashi, MD; Junya Masumoto, MD, PhD; Hirohiko Ise, PhD; Junji Sagara, PhD; Jun Nakayama, MD, PhD; Shun'ichiro Taniguchi, PhD; Uichi Ikeda, MD, PhD

From the Departments of Cardiovascular Medicine (N.Y., M.T., H.M., Y.S., H.I., U.I.) and Molecular Oncology (Y.T., J.S., S.T.), Shinshu University Graduate School of Medicine, and Department of Pathology (J.M., J.N.), Shinshu University School of Medicine, Matsumoto, Japan.

Correspondence to Masafumi Takahashi, MD, PhD, Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail masafumi{at}shinshu-u.ac.jp

Received June 12, 2007; accepted March 31, 2008.

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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