© 1997 American Heart Association, Inc.
Articles |
Effect of Probucol Treatment on Gene Expression of VCAM-1, MCP-1, and M-CSF in the Aortic Wall of LDL Receptor–Deficient Rabbits During Early Atherogenesis
From the Department of Medicine, University of California San Diego, La Jolla, Calif.
Correspondence to Joachim Fruebis, PhD, University of California San Diego, Department of Medicine, 0682, 9500 Gilman Dr, BSB 1080, La Jolla, CA 92093-0682. E-mail jfruebis{at}ucsd.edu
Abstract
Abstract Probucol is a potent inhibitor of atherosclerosis in animal models. However, the mechanism of its antiatherogenic effect is not known. To investigate the effects of probucol on gene expression of VCAM-1, MCP-1, and M-CSF in vivo during the early stages of atherogenesis, we determined gene expression in 12 control WHHL rabbits and 12 WHHL rabbits fed 1% probucol from age 3 weeks. Three animals from each group were killed at 6, 9, 12, and 18 weeks of age. Two intimal/medial segments of the thoracic aorta, each comprising the orifices of a pair of intercostal arteries, were analyzed by semiquantitative RT-PCR using GAPDH as an internal standard. A third segment located between these two segments was studied by immunocytochemistry. A basal level of VCAM-1 gene expression was observed in lesion-free aortas of both treated and untreated WHHL rabbits (and in normal NZW aortas). Immunocytochemistry showed some VCAM-1 protein in normal arteries and confirmed that VCAM-1 protein expression generally correlated with gene expression. In the untreated WHHL rabbits, a marked upregulation of VCAM-1 expression was observed at 18 weeks. To correlate gene expression with intimal monocyte/macrophages in each animal, the macrophage area was determined by morphometry of immunostained sections. In addition, a scoring system of lesions was used. VCAM-1 expression showed a highly significant correlation with the extent of intimal macrophage presence (P<.001). A lesser degree of correlation between gene expression and macrophage accumulation was also seen for MCP-1. In contrast, M-CSF expression remained constant over the entire study period and showed no correlation with the intimal macrophage accumulation. Probucol treatment completely prevented lesion formation in all animals up to 18 weeks of age. Probucol reduced the level of basal VCAM-1 expression and prevented its upregulation. MCP-1 expression was not affected by probucol treatment, whereas M-CSF expression was significantly lowered by probucol. Our results support the idea that VCAM-1 plays an important role in early atherogenesis and suggest that the antiatherogenic effect of probucol may in part be due to a downregulation of VCAM-1. Reduction of the basal level of M-CSF gene expression by probucol treatment may also contribute to its ability to inhibit atherogenesis.
Key Words: arteriosclerosis • oxidation • antioxidants • PCR • immunocytochemistry
This article has been cited by other articles:
 |
|
 |
|
  B. J. Wu, N. Di Girolamo, K. Beck, C. G. Hanratty, K. Choy, J. Y. Hou, M. R. Ward, and R. Stocker Probucol [4,4'-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 477 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Boisvert, D. M. Rose, K. A. Johnson, M. E. Fuentes, S. A. Lira, L. K. Curtiss, and R. A. Terkeltaub Up-Regulated Expression of the CXCR2 Ligand KC/GRO-{alpha} in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression Am. J. Pathol., April 1, 2006; 168(4): 1385 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Sun, S.-J. Hu, L.-H. Wang, Y. Hu, and J.-Y. Zhou Effect of {beta}-Blockers on Cardiac Function and Calcium Handling Protein in Postinfarction Heart Failure Rats Chest, September 1, 2005; 128(3): 1812 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-W. Chen, F.-Y. Lin, Y.-H. Chen, T.-C. Wu, Y.-L. Chen, and S.-J. Lin Carvedilol Inhibits Tumor Necrosis Factor-{alpha}-Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2075 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kunsch, J. Luchoomun, J. Y. Grey, L. K. Olliff, L. B. Saint, R. F. Arrendale, M. A. Wasserman, U. Saxena, and R. M. Medford Selective Inhibition of Endothelial and Monocyte Redox-Sensitive Genes by AGI-1067: A Novel Antioxidant and Anti-Inflammatory Agent J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 820 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ruan, H. J. Pownall, and H. F. Lodish Troglitazone Antagonizes Tumor Necrosis Factor-{alpha}-induced Reprogramming of Adipocyte Gene Expression by Inhibiting the Transcriptional Regulatory Functions of NF-{kappa}B J. Biol. Chem., July 18, 2003; 278(30): 28181 - 28192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Tanaka, H. Shimokawa, H. Kamiuneten, Y. Eto, Y. Matsumoto, K. Morishige, G. Koike, M. Yoshinaga, K. Egashira, O. Tokunaga, et al. Disparity of MCP-1 mRNA and Protein Expressions Between the Carotid Artery and the Aorta in WHHL Rabbits: One Aspect Involved in the Regional Difference in Atherosclerosis Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 244 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Stork, K. Baumann, C. von Schacky, and P. Angerer The effect of 17{beta}-estradiol on MCP-1 serum levels in postmenopausal women Cardiovasc Res, February 15, 2002; 53(3): 642 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. NAPOLI, O. QUEHENBERGER, F. DE NIGRIS, P. ABETE, C. K. GLASS, and W. PALINSKI Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells FASEB J, October 1, 2000; 14(13): 1996 - 2007. [Abstract] [Full Text]
|
|
|
|
|
|
P. K. Witting, K. Pettersson, J. Letters, and R. Stocker Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2000; 20 (8): e26 - e33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. De Keulenaer, M. Ushio-Fukai, Q. Yin, A. B. Chung, P. R. Lyons, N. Ishizaka, K. Rengarajan, W. R. Taylor, R. W. Alexander, and K. K. Griendling Convergence of Redox-Sensitive and Mitogen-Activated Protein Kinase Signaling Pathways in Tumor Necrosis Factor-{alpha}-Mediated Monocyte Chemoattractant Protein-1 Induction in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 385 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Collins, R. Velji, N. V. Guevara, M. J. Hicks, L. Chan, and A. L. Beaudet P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice J. Exp. Med., January 3, 2000; 191(1): 189 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Koh, A. Blum, L. Hathaway, R. Mincemoyer, G. Csako, M. A. Waclawiw, J. A. Panza, and R. O. Cannon III Vascular Effects of Estrogen and Vitamin E Therapies in Postmenopausal Women Circulation, November 2, 1999; 100(18): 1851 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Fruebis, M. Silvestre, D. Shelton, C. Napoli, and W. Palinski Inhibition of VCAM-1 expression in the arterial wall is shared by structurally different antioxidants that reduce early atherosclerosis in NZW rabbits J. Lipid Res., November 1, 1999; 40(11): 1958 - 1966. [Abstract] [Full Text]
|
|
|
|
|
|
G. A. Truskey, R. A. Herrmann, J. Kait, and K. M. Barber Focal Increases in Vascular Cell Adhesion Molecule-1 and Intimal Macrophages at Atherosclerosis-Susceptible Sites in the Rabbit Aorta After Short-Term Cholesterol Feeding Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 393 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ross Atherosclerosis -- An Inflammatory Disease N. Engl. J. Med., January 14, 1999; 340(2): 115 - 126. [Full Text] [PDF]
|
|
|
|
|
|
Z. S. Galis, K. Asanuma, D. Godin, and X. Meng N-Acetyl-Cysteine Decreases the Matrix-Degrading Capacity of Macrophage-Derived Foam Cells : New Target for Antioxidant Therapy? Circulation, June 23, 1998; 97(24): 2445 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Bird, R. K. Tangirala, J. Fruebis, D. Steinberg, J. L. Witztum, and W. Palinski Effect of probucol on LDL oxidation and atherosclerosis in LDL receptor-deficient mice J. Lipid Res., May 1, 1998; 39(5): 1079 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Takabe, T. Kodama, T. Hamakubo, K. Tanaka, T. Suzuki, H. Aburatani, N. Matsukawa, and N. Noguchi Anti-atherogenic Antioxidants Regulate the Expression and Function of Proteasome alpha -Type Subunits in Human Endothelial Cells J. Biol. Chem., October 26, 2001; 276(44): 40497 - 40501. [Abstract] [Full Text] [PDF]
|
|