Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development

Hidehiro Kaneko, Toshihisa Anzai, Keisuke Horiuchi, Takashi Kohno, Toshiyuki Nagai, Atsushi Anzai, Toshiyuki Takahashi, Aya Sasaki, Masayuki Shimoda, Yuichiro Maekawa, Hideyuki Shimizu, Tsutomu Yoshikawa, Yasunori Okada, Ryohei Yozu, Keiichi Fukuda

Research output: Contribution to journalArticle

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Abstract

Objective: Tumor necrosis factor (TNF)-α is known to be elevated in plasma and the aorta in abdominal aortic aneurysm (AAA) patients. We sought to clarify the role of TNF-α converting enzyme (Tace), which cleaves the transmembrane precursor of TNF-α, in AAA development. Methods: We obtained aortic sample of AAA during surgical operation to assess the histological features and protein expression of human AAA. AAA was induced in mice with temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene (TaceMx1) and in wild-type littermates (CON) by periaortic application of CaCl 2 (AAA/TaceMx1, AAA/CON). Results: Tace expression was increased in human AAA samples as compared with normal aorta. Six weeks postoperatively, aortic diameter in AAA/TaceMx1 was decreased than in AAA/CON in association with attenuated TNF-α expression and extracellular matrix disruption. Increased activities of matrix metalloproteinase (MMP)-9 and MMP-2, numbers of Mac-2-positive macrophages, CD3-positive T lymphocytes and CD31-positive vessels in periaortic tissues, mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α, vascular endothelial growth factor-A, p47 and glutathione peroxidases, and protein expression of phospho-c-Jun N-terminal kinase in AAA were all attenuated by Tace deletion. Protein expression of transforming growth factor (TGF)-β1 was upregulated by Tace deletion in sham-operated mice. TGF-β1 expression was further increased in AAA/TaceMx1. Conclusions: Tace was overexpressed in the aortic wall in human and experimental AAA. Temporal systemic deletion of Tace prevented AAA development in association with attenuating inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption, suggesting a crucial role of Tace in AAA development.

Original languageEnglish
Pages (from-to)470-478
Number of pages9
JournalAtherosclerosis
Volume218
Issue number2
DOIs
Publication statusPublished - 2011 Oct

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Abdominal Aortic Aneurysm
Tumor Necrosis Factor-alpha
Enzymes
Transforming Growth Factors
Extracellular Matrix
Aorta
Proteins
JNK Mitogen-Activated Protein Kinases
Chemokine CCL2
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Glutathione Peroxidase
Transgenes
Vascular Endothelial Growth Factor A

Keywords

  • Abdominal aortic aneurysm
  • Extracellular matrix
  • Inflammation
  • Macrophages
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development. / Kaneko, Hidehiro; Anzai, Toshihisa; Horiuchi, Keisuke; Kohno, Takashi; Nagai, Toshiyuki; Anzai, Atsushi; Takahashi, Toshiyuki; Sasaki, Aya; Shimoda, Masayuki; Maekawa, Yuichiro; Shimizu, Hideyuki; Yoshikawa, Tsutomu; Okada, Yasunori; Yozu, Ryohei; Fukuda, Keiichi.

In: Atherosclerosis, Vol. 218, No. 2, 10.2011, p. 470-478.

Research output: Contribution to journalArticle

Kaneko, H, Anzai, T, Horiuchi, K, Kohno, T, Nagai, T, Anzai, A, Takahashi, T, Sasaki, A, Shimoda, M, Maekawa, Y, Shimizu, H, Yoshikawa, T, Okada, Y, Yozu, R & Fukuda, K 2011, 'Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development', Atherosclerosis, vol. 218, no. 2, pp. 470-478. https://doi.org/10.1016/j.atherosclerosis.2011.06.008
Kaneko, Hidehiro ; Anzai, Toshihisa ; Horiuchi, Keisuke ; Kohno, Takashi ; Nagai, Toshiyuki ; Anzai, Atsushi ; Takahashi, Toshiyuki ; Sasaki, Aya ; Shimoda, Masayuki ; Maekawa, Yuichiro ; Shimizu, Hideyuki ; Yoshikawa, Tsutomu ; Okada, Yasunori ; Yozu, Ryohei ; Fukuda, Keiichi. / Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development. In: Atherosclerosis. 2011 ; Vol. 218, No. 2. pp. 470-478.
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AU - Nagai, Toshiyuki

AU - Anzai, Atsushi

AU - Takahashi, Toshiyuki

AU - Sasaki, Aya

AU - Shimoda, Masayuki

AU - Maekawa, Yuichiro

AU - Shimizu, Hideyuki

AU - Yoshikawa, Tsutomu

AU - Okada, Yasunori

AU - Yozu, Ryohei

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