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(Stroke. 2008;39:2853.)
© 2008 American Heart Association, Inc.

Original Contributions

Targeted Disruption of Hsp110/105 Gene Protects Against Ischemic Stress

Junji Nakamura, MS; Motoaki Fujimoto, MD; Kunihiko Yasuda, PhD; Kiyoshi Takeda, MD, PhD; Shizuo Akira, MD, PhD; Takumi Hatayama, MD, PhD; Yasushi Takagi, MD, PhD; Kazuhiko Nozaki, MD, PhD; Nobuko Hosokawa, MD, PhD Kazuhiro Nagata, PhD

From the Department of Molecular and Cellular Biology (J.N., N.H., K.N.), Institute for Frontier Medical Sciences, Department of Neurosurgery (M.F., Y.T., K.N.), Graduate School of Medicine, and Laboratory of Functional Biology (K.Y.), Graduate School of Biostudies, Kyoto University, Kyoto, Japan; CREST (J.N., N.H., K.N.), Japan Science and Technology Agency, Saitama, Laboratory of Immune Regulation (K.T.), Graduate School of Medicine, and Department of Host Defense (S.A.), Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and the Department of Biochemistry (T.H.), Kyoto Pharmaceutical University, Kyoto, Japan.

Correspondence to Kazuhiro Nagata, PhD, Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail nagata{at}frontier.kyoto-u.ac.jp

Background and Purpose— Hsp110/105 belongs to the HSP110 heat shock protein family, which is a subgroup of the HSP70 family. In mammals, Hsp110/105 is constitutively expressed but exhibits particularly high levels in the brain. It has recently been shown that both Hsp110/105 and Hsp70 are elevated after cerebral ischemia. To study the physiological role of this protein in vivo, we generated hsp110/105 knockout (KO) mice and investigate the effect of reduced Hsp110/105 levels on focal cerebral ischemia.

Methods— hsp110/105 KO and wild-type mice were subjected to 30 minutes of transient middle cerebral artery occlusion followed by reperfusion for 24 hours. The infarct volume and neurological scores were measured and compared. The Hsp70 chaperone activity of thermally denatured firefly luciferase was measured in hsp110/105 KO embryonic fibroblasts.

Results— The infarct volume and neurological deficit scores were significantly (P<0.05) reduced in hsp110/105 KO mice compared with wild-type controls. In addition, hsp110/105 KO embryonic fibroblasts exhibited a dose-dependent suppression of Hsp70 chaperone activity by the presence of Hsp110/105.

Conclusions— These results demonstrate that hsp110/105 KO mice are resistant to ischemic injury and that the protective effects of hsp110/105 deficiency in cerebral ischemia may partly be mediated by an increase in the chaperone activity of Hsp70.

Key Words: cerebral ischemia • focal • Hsp70/Hsc70 chaperone activity • Hsp110/105 • knockout • mice