Recombinant human thrombomodulin suppresses experimental abdominal aortic aneurysms induced by calcium chloride in mice

Chao-Han Lai, Guey Yueh Shi, Fang Tzu Lee, Cheng Hsiang Kuo, Tsung Lin Cheng, Bi Ing Chang, Chih Yuan Ma, Fu Chih Hsu, Yu Jen Yang, Hua-Lin Wu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1103-1110
Number of pages8
JournalAnnals of Surgery
Volume258
Issue number6
DOIs
Publication statusPublished - 2013 Dec 1

Fingerprint

Calcium Chloride
Abdominal Aortic Aneurysm
Macrophages
Thrombomodulin
Inflammation
Aneurysm
Extracellular Matrix
Cytokines
Vascular Calcification
Macrophage Activation
human THBD protein
Matrix Metalloproteinases
Blood Vessels
Dilatation
Glycoproteins
Anti-Inflammatory Agents
Advanced Glycosylation End Product-Specific Receptor

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Lai, Chao-Han ; Shi, Guey Yueh ; Lee, Fang Tzu ; Kuo, Cheng Hsiang ; Cheng, Tsung Lin ; Chang, Bi Ing ; Ma, Chih Yuan ; Hsu, Fu Chih ; Yang, Yu Jen ; Wu, Hua-Lin. / Recombinant human thrombomodulin suppresses experimental abdominal aortic aneurysms induced by calcium chloride in mice. In: Annals of Surgery. 2013 ; Vol. 258, No. 6. pp. 1103-1110.
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abstract = "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.",
author = "Chao-Han Lai and Shi, {Guey Yueh} and Lee, {Fang Tzu} and Kuo, {Cheng Hsiang} and Cheng, {Tsung Lin} and Chang, {Bi Ing} and Ma, {Chih Yuan} and Hsu, {Fu Chih} and Yang, {Yu Jen} and Hua-Lin Wu",
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Recombinant human thrombomodulin suppresses experimental abdominal aortic aneurysms induced by calcium chloride in mice. / Lai, Chao-Han; Shi, Guey Yueh; Lee, Fang Tzu; Kuo, Cheng Hsiang; Cheng, Tsung Lin; Chang, Bi Ing; Ma, Chih Yuan; Hsu, Fu Chih; Yang, Yu Jen; Wu, Hua-Lin.

In: Annals of Surgery, Vol. 258, No. 6, 01.12.2013, p. 1103-1110.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recombinant human thrombomodulin suppresses experimental abdominal aortic aneurysms induced by calcium chloride in mice

AU - Lai, Chao-Han

AU - Shi, Guey Yueh

AU - Lee, Fang Tzu

AU - Kuo, Cheng Hsiang

AU - Cheng, Tsung Lin

AU - Chang, Bi Ing

AU - Ma, Chih Yuan

AU - Hsu, Fu Chih

AU - Yang, Yu Jen

AU - Wu, Hua-Lin

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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.

AB - 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.

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