© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Oxidized LDL Regulates Vascular Endothelial Growth Factor Expression in Human Macrophages and Endothelial Cells Through Activation of Peroxisome Proliferator–Activated Receptor-
From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Hiroshi Itoh, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp
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-
(PPAR) is expressed not only in adipocytes but also in
monocytes/macrophages and has suggested that PPAR 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
PPAR ligands. Therefore, we investigated the involvement of PPAR
in the regulation of VEGF by Ox-LDL. PPAR 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
PPAR activators, troglitazone (TRO), and
15-deoxy-
12,14-prostaglandin
J2 (PGJ2). In contrast, VEGF expression in
another monocyte/macrophage cell line, human histiocytic
lymphoma cells (U937), which lacks PPAR expression, was not
augmented by TRO or PGJ2. We established the U937 cell line, which
permanently expresses PPAR (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
PPAR.
Key Words: vascular endothelial growth factors • atherosclerosis • macrophages • endothelial cells • peroxisome proliferator–activated receptor-
This article has been cited by other articles:
 |
|
 |
|
  J. Barlic, W. Zhu, and P. M. Murphy Atherogenic Lipids Induce High-Density Lipoprotein Uptake and Cholesterol Efflux in Human Macrophages by Up-Regulating Transmembrane Chemokine CXCL16 without Engaging CXCL16-Dependent Cell Adhesion J. Immunol., June 15, 2009; 182(12): 7928 - 7936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mallika, B. Goswami, and M. Rajappa Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective Angiology, November 1, 2007; 58(5): 513 - 522. [Abstract] [PDF]
|
|
|
|
 |
|
 J. L. Mehta Oxidized or Native Low-Density Lipoprotein Cholesterol: Which Is More Important in Atherogenesis? J. Am. Coll. Cardiol., September 5, 2006; 48(5): 980 - 982. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Alfranca, M. A. Iniguez, M. Fresno, and J. M. Redondo Prostanoid signal transduction and gene expression in the endothelium: Role in cardiovascular diseases Cardiovasc Res, June 1, 2006; 70(3): 446 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dulak, S. P Schwarzacher, R. H Zwick, H. Alber, G. Millonig, C. Weiss, H. Hugel, M. Frick, A. Jozkowicz, O. Pachinger, et al. Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits Vascular Medicine, November 1, 2005; 10(4): 285 - 291. [Abstract] [PDF]
|
|
|
|
 |
|
 W. Song, J. L. Barth, Y. Yu, K. Lu, A. Dashti, Y. Huang, C. K. Gittinger, W. S. Argraves, and T. J. Lyons Effects of Oxidized and Glycated LDL on Gene Expression in Human Retinal Capillary Pericytes Invest. Ophthalmol. Vis. Sci., August 1, 2005; 46(8): 2974 - 2982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hamerman Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies QJM, July 1, 2005; 98(7): 467 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Patel, K. L Wyne, and D. K McGuire Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence? Diabetes and Vascular Disease Research, May 1, 2005; 2(2): 61 - 66. [Abstract] [PDF]
|
|
|
|
|
|
J. A. Rodriguez, B. Nespereira, M. Perez-Ilzarbe, E. Eguinoa, and J. A. Paramo Vitamins C and E prevent endothelial VEGF and VEGFR-2 overexpression induced by porcine hypercholesterolemic LDL Cardiovasc Res, February 15, 2005; 65(3): 665 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Friday, J. Glass, and F. Turturro Troglitazone Exerts a Cell-Dependent Effect on the Extracellular Secretion of VEGF165 Independently from the Rapamycin Sensitivity or the Level of eIF4E Expression in AML-Derived Cells. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 4363 - 4363. [Abstract]
|
|
|
|
 |
|
 M. Negishi, H. Shimizu, S. Okada, A. Kuwabara, F. Okajima, and M. Mori 9HODE Stimulates Cell Proliferation and Extracellular Matrix Synthesis in Human Mesangial Cells via PPAR{gamma} Experimental Biology and Medicine, November 1, 2004; 229(10): 1053 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Grau, M. A. Iniguez, and M. Fresno Inhibition of Activator Protein 1 Activation, Vascular Endothelial Growth Factor, and Cyclooxygenase-2 Expression by 15-Deoxy-{Delta}12,14-Prostaglandin J2 in Colon Carcinoma Cells: Evidence for a Redox-Sensitive Peroxisome Proliferator-Activated Receptor-{gamma}-Independent Mechanism Cancer Res., August 1, 2004; 64(15): 5162 - 5171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Chade, M. D. Bentley, X. Zhu, M. Rodriguez-Porcel, S. Niemeyer, B. Amores-Arriaga, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1816 - 1825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Walczak, S. B. Joseph, B. A. Laffitte, A. Castrillo, L. Pei, and P. Tontonoz Transcription of the Vascular Endothelial Growth Factor Gene in Macrophages Is Regulated by Liver X Receptors J. Biol. Chem., March 12, 2004; 279(11): 9905 - 9911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. E. Konstantinov, J. G. Coles, C. Boscarino, M. Takahashi, J. Goncalves, J. Ritter, and G. S. Van Arsdell Gene expression profiles in children undergoing cardiac surgery for right heart obstructive lesions J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 746 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Cho, Y. J. Choi, S. A. Jo, and I. Jo Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone: EVIDENCE FOR INVOLVEMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) {gamma}-DEPENDENT AND PPAR{gamma}-INDEPENDENT SIGNALING PATHWAYS J. Biol. Chem., January 23, 2004; 279(4): 2499 - 2506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Klein, J. Allard, Z. Avnur, T. Nikolcheva, D. Rotstein, A. S. Carlos, M. Shea, R. V. Waters, J. K. Belknap, G. Peltz, et al. Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15 Science, January 9, 2004; 303(5655): 229 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Lutgendorf, S. Cole, E. Costanzo, S. Bradley, J. Coffin, S. Jabbari, K. Rainwater, J. M. Ritchie, M. Yang, and A. K. Sood Stress-Related Mediators Stimulate Vascular Endothelial Growth Factor Secretion by Two Ovarian Cancer Cell Lines Clin. Cancer Res., October 1, 2003; 9(12): 4514 - 4521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fu, J. Zhang, Y. Lin, X. Zhu, M. U. Ehrengruber, and Y. E. Chen Early Growth Response Factor-1 Is a Critical Transcriptional Mediator of Peroxisome Proliferator-activated Receptor-gamma 1 Gene Expression in Human Aortic Smooth Muscle Cells J. Biol. Chem., July 19, 2002; 277(30): 26808 - 26814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fauconnet, I. Lascombe, E. Chabannes, G.-L. Adessi, B. Desvergne, W. Wahli, and H. Bittard Differential Regulation of Vascular Endothelial Growth Factor Expression by Peroxisome Proliferator-activated Receptors in Bladder Cancer Cells J. Biol. Chem., June 21, 2002; 277(26): 23534 - 23543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Franz Alber, J. Dulak, M. Frick, W. Dichtl, S. Paul Schwarzacher, O. Pachinger, and F. Weidinger Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1951 - 1955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Molavi, N. Rasouli, and J. L. Mehta Peroxisome Proliferator-Activated Receptor Ligands as Antiatherogenic Agents: Panacea or Another Pandora's Box? Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 1 - 8. [Abstract] [PDF]
|
|
|
|
|
|
J. Dulak, A. Jozkowicz, M. Frick, H. F. Alber, W. Dichtl, S. P. Schwarzacher, O. Pachinger, and F. Weidinger Vascular endothelial growth factor: angiogenesis, atherogenesis or both? J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2137 - 2138. [Full Text] [PDF]
|
|