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Recombinant Human Thrombomodulin Suppresses Experimental Abdominal Aortic Aneurysms Induced by Calcium Chloride in Mice

Lai, Chao-Han MD*,†,‡; Shi, Guey-Yueh PhD†,§; Lee, Fang-Tzu MS†,§; Kuo, Cheng-Hsiang PhD†,§; Cheng, Tsung-Lin PhD†,§; Chang, Bi-Ing MS†,§; Ma, Chih-Yuan PhD†,§; Hsu, Fu-Chih MS†,§; Yang, Yu-Jen MD, PhD†,‡; Wu, Hua-Lin PhD†,§

doi: 10.1097/SLA.0b013e31827df7cb
Original Articles

Objective: To investigate whether recombinant thrombomodulin containing all the extracellular domains (rTMD123) has therapeutic potential against aneurysm development.

Summary Background Data: The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by chronic inflammation and proteolytic degradation of extracellular matrix. Thrombomodulin, a transmembrane glycoprotein, exerts anti-inflammatory activities such as inhibition of cytokine production and sequestration of proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end product (RAGE) that may sustain inflammation and tissue damage.

Methods: The in vivo effects of treatment and posttreatment with rTMD123 on aortic dilatation were measured using the CaCl2-induced AAA model in mice.

Results: Characterization of the CaCl2-induced model revealed that HMGB1 and RAGE, both localized mainly to macrophages, were persistently upregulated during a 28-day period of AAA development. In vitro, rTMD123-HMGB1 interaction prevented HMGB1 binding to macrophages, thereby prohibiting activation of HMGB1-RAGE signaling in macrophages. In vivo, short-term treatment with rTMD123 upon AAA induction suppressed the levels of proinflammatory cytokines, HMGB1, and RAGE in the aortic tissue; reduced the infiltrating macrophage number; and finally attenuated matrix metalloproteinase production, extracellular matrix destruction, and AAA formation without disturbing vascular calcification. Consistently, posttreatment with rTMD123 seven days after AAA induction alleviated vascular inflammation and retarded AAA progression.

Conclusions: These data suggest that rTMD123 confers protection against AAA development. The mechanism of action may be associated with reduction of proinflammatory mediators, blockade of macrophage recruitment, and suppression of HMGB1-RAGE signaling involved in aneurysm formation and downstream macrophage activation.

This study reveals that recombinant thrombomodulin (rTMD123), a pleiotropic anti-inflammatory agent, confers protection against CaCl2-induced abdominal aortic aneurysms in mice mainly through inhibition of cytokine production and high-mobility group box 1 (HMGB1)-receptor for advanced glycation end (RAGE) product signaling and thus suggests therapeutic potential of rTMD123 to suppress aneurysm development.

*Institute of Clinical Medicine

Cardiovascular Research Center

Departments of Surgery; and

§Biochemistry and Molecular Biology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Reprints: Hua-Lin Wu, PhD, or Guey-Yueh Shi, PhD, Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan, No. 1, University Road, Tainan 701, Taiwan. E-mail: halnwu@mail.ncku.edu.tw or gyshi@mail.ncku.edu.tw.

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Disclosure: This study was supported by grants from the National Science Council, Executive Yuan, Taiwan (NSC99-2314-B-006-025-MY2 to C. H. L., NSC99-2628-B-006-003-MY3 to G. Y. S., and NSC99-2320-B-006-008-MY3 to H. L. W.), a grant from National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-10004009 to C. H. L.), and a National Cheng Kung University Aim for the Top University Plan grant from the Ministry of Education, Taiwan (to G. Y. S. and H. L. W.). For the remaining authors, no conflicts of interest were declared.

© 2013 by Lippincott Williams & Wilkins.