Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression

Eiji Horio, Tsuyoshi Kadomatsu, Keishi Miyata, Yasumichi Arai, Kentaro Hosokawa, Yasufumi Doi, Toshiharu Ninomiya, Haruki Horiguchi, Motoyoshi Endo, Mitsuhisa Tabata, Hirokazu Tazume, Zhe Tian, Otowa Takahashi, Kazutoyo Terada, Motohiro Takeya, Hiroyuki Hao, Nobuyoshi Hirose, Takashi Minami, Toshio Suda, Yutaka Kiyohara & 3 others Hisao Ogawa, Koichi Kaikita, Yuichi Oike

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Objective-cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and results-Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE-/-/Angptl2-/-) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE-/- mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE-/-/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2-/- mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions-Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

Original languageEnglish
Pages (from-to)790-800
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number4
DOIs
Publication statusPublished - 2014

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Angiopoietins
Blood Vessels
Atherosclerosis
Endothelial Cells
Inflammation
Macrophages
Apolipoproteins E
Proteins
Atherosclerotic Plaques
Monocytes
Cardiovascular Diseases
Protein Deficiency
High Fat Diet
Chemotaxis
Bone Marrow Transplantation
Transgenic Mice
Endothelium
Cause of Death
Nitric Oxide
Pathology

Keywords

  • atherosclerosis
  • cardiovascular diseases
  • endothelium-derived vasoconstrictor factors
  • inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. / Horio, Eiji; Kadomatsu, Tsuyoshi; Miyata, Keishi; Arai, Yasumichi; Hosokawa, Kentaro; Doi, Yasufumi; Ninomiya, Toshiharu; Horiguchi, Haruki; Endo, Motoyoshi; Tabata, Mitsuhisa; Tazume, Hirokazu; Tian, Zhe; Takahashi, Otowa; Terada, Kazutoyo; Takeya, Motohiro; Hao, Hiroyuki; Hirose, Nobuyoshi; Minami, Takashi; Suda, Toshio; Kiyohara, Yutaka; Ogawa, Hisao; Kaikita, Koichi; Oike, Yuichi.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 34, No. 4, 2014, p. 790-800.

Research output: Contribution to journalArticle

Horio, E, Kadomatsu, T, Miyata, K, Arai, Y, Hosokawa, K, Doi, Y, Ninomiya, T, Horiguchi, H, Endo, M, Tabata, M, Tazume, H, Tian, Z, Takahashi, O, Terada, K, Takeya, M, Hao, H, Hirose, N, Minami, T, Suda, T, Kiyohara, Y, Ogawa, H, Kaikita, K & Oike, Y 2014, 'Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 4, pp. 790-800. https://doi.org/10.1161/ATVBAHA.113.303116
Horio, Eiji ; Kadomatsu, Tsuyoshi ; Miyata, Keishi ; Arai, Yasumichi ; Hosokawa, Kentaro ; Doi, Yasufumi ; Ninomiya, Toshiharu ; Horiguchi, Haruki ; Endo, Motoyoshi ; Tabata, Mitsuhisa ; Tazume, Hirokazu ; Tian, Zhe ; Takahashi, Otowa ; Terada, Kazutoyo ; Takeya, Motohiro ; Hao, Hiroyuki ; Hirose, Nobuyoshi ; Minami, Takashi ; Suda, Toshio ; Kiyohara, Yutaka ; Ogawa, Hisao ; Kaikita, Koichi ; Oike, Yuichi. / Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2014 ; Vol. 34, No. 4. pp. 790-800.
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AU - Horio, Eiji

AU - Kadomatsu, Tsuyoshi

AU - Miyata, Keishi

AU - Arai, Yasumichi

AU - Hosokawa, Kentaro

AU - Doi, Yasufumi

AU - Ninomiya, Toshiharu

AU - Horiguchi, Haruki

AU - Endo, Motoyoshi

AU - Tabata, Mitsuhisa

AU - Tazume, Hirokazu

AU - Tian, Zhe

AU - Takahashi, Otowa

AU - Terada, Kazutoyo

AU - Takeya, Motohiro

AU - Hao, Hiroyuki

AU - Hirose, Nobuyoshi

AU - Minami, Takashi

AU - Suda, Toshio

AU - Kiyohara, Yutaka

AU - Ogawa, Hisao

AU - Kaikita, Koichi

AU - Oike, Yuichi

PY - 2014

Y1 - 2014

N2 - Objective-cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and results-Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE-/-/Angptl2-/-) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE-/- mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE-/-/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2-/- mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions-Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

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