Volume 25 Issue 1 - October 11, 2013 PDF
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Recombinant Human Thrombomodulin Suppresses Experimental Abdominal Aortic Aneurysms Induced by Calcium Chloride in Mice
Chao-Han Lai, MD1,2,4, Guey-Yueh Shi, PhD2,3, Fang-Tzu Lee, MS2,3, Cheng-Hsiang Kuo, PhD2,3, Tsung-Lin Cheng, PhD2,3, Bi-Ing Chang, MS2,3, Chih-Yuan Ma, PhD2,3, Fu-Chih Hsu, MS2,3, Yu-Jen Yang, MD, PhD2,4, Hua-Lin Wu, PhD2,3,*
1 Institute of Clinical Medicine, 2 Cardiovascular Research Center, 3 Department of Biochemistry and Molecular Biology, and 4 Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
 
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Abdominal aortic aneurysm (AAA) represents a degenerative process of the abdominal aorta and is a common disease in the elderly population with estimates of prevalence ranging 5% to 10%. Despite an improved understanding of the pathophysiology, physicians remain incapable of modifying the natural history of AAA development. Therapeutic strategies to alter the course of AAA must be aimed at the underlying events that promote AAA development.

The pathogenesis of AAA is characterized by chronic inflammation and proteolytic degradation of extracellular matrix (ECM). Thrombomodulin (TM), 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. We aimed to investigate the hypothesis that recombinant TM containing all the extracellular domains (rTMD123) might have therapeutic potential against aneurysm development.

Characterization of the CaCl2-induced AAA model in mice 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, ECM destruction and AAA formation (Figure 1) without disturbing vascular calcification. Consistently, post-treatment with rTMD123 alleviated vascular inflammation and retarded AAA progression.
Figure 1. Analysis of aortic samples obtained on day 28 showed that rTMD123 treatment prevents AAA formation.

These data suggest that rTMD123 confers protection against AAA development. The mechanism of action (Figure 2) 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.
Figure 2. Possible mechanisms of rTMD123 in suppression of the development of AAA. The schematic diagram shows that rTMD123 confers protection against both inflammation and proteolysis.
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