Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ

Mayumi Inoue, Hiroshi Itoh, Tokuji Tanaka, Tae Hwa Chun, Kentaro Doi, Yasutomo Fukunaga, Naoki Sawada, Jun Yamshita, Ken Masatsugu, Takatoshi Saito, Satsuki Sakaguchi, Masakatsu Sone, Ken Ichi Yamahara, Takami Yurugi, Kazuwa Nakao

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-γ (PPARγ) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARγ may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARγ ligands. Therefore, we investigated the involvement of PPARγ in the regulation of VEGF by Ox-LDL. PPARγ expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 μg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARγ activators, troglitazone (TRO), and 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARγ expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARγ (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARγ.

Original languageEnglish
Pages (from-to)560-566
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume21
Issue number4
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Vascular Endothelial Growth Factor A
Endothelial Cells
Macrophages
troglitazone
Monocytes
Coronary Vessels
U937 Cells
oxidized low density lipoprotein
Cell Line
Atherosclerosis
Leukemia, Monocytic, Acute
Messenger RNA
Lymphoma, Large B-Cell, Diffuse
Angiogenesis Inducing Agents
Capillary Permeability
Adipocytes
Smooth Muscle Myocytes

Keywords

  • Atherosclerosis
  • Endothelial cells
  • Macrophages
  • Peroxisome proliferator-activated receptor-γ
  • Vascular endothelial growth factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ. / Inoue, Mayumi; Itoh, Hiroshi; Tanaka, Tokuji; Chun, Tae Hwa; Doi, Kentaro; Fukunaga, Yasutomo; Sawada, Naoki; Yamshita, Jun; Masatsugu, Ken; Saito, Takatoshi; Sakaguchi, Satsuki; Sone, Masakatsu; Yamahara, Ken Ichi; Yurugi, Takami; Nakao, Kazuwa.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 21, No. 4, 2001, p. 560-566.

Research output: Contribution to journalArticle

Inoue, M, Itoh, H, Tanaka, T, Chun, TH, Doi, K, Fukunaga, Y, Sawada, N, Yamshita, J, Masatsugu, K, Saito, T, Sakaguchi, S, Sone, M, Yamahara, KI, Yurugi, T & Nakao, K 2001, 'Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 4, pp. 560-566.
Inoue, Mayumi ; Itoh, Hiroshi ; Tanaka, Tokuji ; Chun, Tae Hwa ; Doi, Kentaro ; Fukunaga, Yasutomo ; Sawada, Naoki ; Yamshita, Jun ; Masatsugu, Ken ; Saito, Takatoshi ; Sakaguchi, Satsuki ; Sone, Masakatsu ; Yamahara, Ken Ichi ; Yurugi, Takami ; Nakao, Kazuwa. / Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 ; Vol. 21, No. 4. pp. 560-566.
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abstract = "Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-γ (PPARγ) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARγ may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARγ ligands. Therefore, we investigated the involvement of PPARγ in the regulation of VEGF by Ox-LDL. PPARγ expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 μg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARγ activators, troglitazone (TRO), and 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARγ expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARγ (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARγ.",
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T1 - Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ

AU - Inoue, Mayumi

AU - Itoh, Hiroshi

AU - Tanaka, Tokuji

AU - Chun, Tae Hwa

AU - Doi, Kentaro

AU - Fukunaga, Yasutomo

AU - Sawada, Naoki

AU - Yamshita, Jun

AU - Masatsugu, Ken

AU - Saito, Takatoshi

AU - Sakaguchi, Satsuki

AU - Sone, Masakatsu

AU - Yamahara, Ken Ichi

AU - Yurugi, Takami

AU - Nakao, Kazuwa

PY - 2001

Y1 - 2001

N2 - Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-γ (PPARγ) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARγ may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARγ ligands. Therefore, we investigated the involvement of PPARγ in the regulation of VEGF by Ox-LDL. PPARγ expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 μg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARγ activators, troglitazone (TRO), and 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARγ expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARγ (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARγ.

AB - Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-γ (PPARγ) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARγ may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARγ ligands. Therefore, we investigated the involvement of PPARγ in the regulation of VEGF by Ox-LDL. PPARγ expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 μg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARγ activators, troglitazone (TRO), and 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARγ expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARγ (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARγ.

KW - Atherosclerosis

KW - Endothelial cells

KW - Macrophages

KW - Peroxisome proliferator-activated receptor-γ

KW - Vascular endothelial growth factors

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