Effects of Dexamethasone on Experimental Atherosclerosis in Cholesterol-fed Rabbits.

Naito, Michitaka; Yasue, Masahiro; Asai, Kuniya; Yamada, Kazuyoshi; Hayashi, Toshio; Kuzuya, Masafumi; Funaki, Chiaki; Yoshimine, Noboru

doi:10.3177/jnsv.38.255

Cited by 37 publications

(27 citation statements)

References 16 publications

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“…6,7) Asai et al have demonstrated in an experimental model that DEX prevents incorporation of modified LDL into macrophages in vitro. 8) We have demonstrated that DEX as well as DP-LDL complex is effective to inhibit foam cell formation of macrophages induced by incubation with native or oxidized LDL in vitro.…”

Section: 79ϯ013 B)mentioning

confidence: 99%

“…6,7) However, although DEX prevents the progression of atherosclerosis by a long-term injection in cholesterol-fed rabbits, some adverse systemic effects of DEX are induced at the same time. 8) Therefore, the DP-LDL complex may be very useful to deliver DEX into atherosclerotic lesions in order to increase the efficacy of the drug and to avoid its adverse systemic effects.…”

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confidence: 99%

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Effect of Dexamethasone Palmitate-Low Density Lipoprotein Complex on Cholesterol Ester Accumulation in Aorta of Atherogenic Model Mice.

Tauchi

Zushida

Chono

et al. 2001

Biological & Pharmaceutical Bulletin

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In order to confirm the efficacy of dexamethasone palmitate (DP)-low density lipoprotein (LDL) complex on experimental atherosclerosis in vivo, we examined whether DP-LDL complex could be effective for cholesterol ester accumulation in the aorta of atherogenic mice. Nonatherogenic and atherogenic mice were fed with normal and atherogenic diet for 14 weeks, respectively. Dexamethasone (DEX), lipid emulsion containing DP (DP-LE), or DP-LDL complex was intravenously injected once a week from 8 to 14 weeks. Cholesterol levels in serum and aorta in the atherogenic mice were significantly higher than those of nonatherogenic mice. Injection of DP-LDL complex significantly reduced cholesterol ester (CE) accumulation in the aorta of atherogenic mice. The reduction of CE accumulation in aorta treated with DP-LDL complexes was 10 and 100 times more potent than that with DP-LE and DEX, respectively. The radioactivity in the aorta of atherogenic mice treated with 3 H-DP-LDL complex was significantly higher than that with 3 H-DP-LE and 3 H-DEX at 24 h after injection. Even 7 d after injection, a significant amount of radioactivity was present only in the aorta of atherogenic mice treated with DP-LDL complex. This result suggests that DP-LDL complex is selectively delivered to the atherogenic lesions in the aorta of atherogenic mice, and then DP released from the complex inhibits CE accumulation in the aortic intima. Therefore, DP-LDL complex may be a good drug-carrier in drug delivery system for atherosclerosis.

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Section: 79ϯ013 B)mentioning

confidence: 99%

mentioning

confidence: 99%

Effect of Dexamethasone Palmitate-Low Density Lipoprotein Complex on Cholesterol Ester Accumulation in Aorta of Atherogenic Model Mice.

Tauchi

Zushida

Chono

et al. 2001

Biological & Pharmaceutical Bulletin

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“…Glucocorticoid treatment is associated with decreased macrophage accumulation in a wide variety of disease states (18) and with decreased intimal hyperplasia in animal models of arterial injury (19 -22). Long term glucocorticoid treatment has been reported to decrease macrophage accumulation and plaque size during the development of atherosclerosis in cholesterol-fed rabbits (23). Short term treatment with dexamethasone (Dex) inhibited MCP-1 expression and macrophage accumulation after femoral arterial injury in cholesterol-fed rabbits (21).…”

mentioning

confidence: 99%

A Novel Role for the Glucocorticoid Receptor in the Regulation of Monocyte Chemoattractant Protein-1 mRNA Stability

Dhawan¹,

Liu²,

Blaxall

et al. 2007

Journal of Biological Chemistry

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Monocyte chemoattractant protein-1 (MCP-1) plays an important role in attracting monocytes to sites of inflammation and is the dominant mediator of macrophage accumulation in atherosclerotic plaques. We have previously shown that glucocorticoids inhibit the secretion of MCP-1 in arterial smooth muscle cells (SMC) by markedly decreasing MCP-1 mRNA stability. We now report that the destabilization of MCP-1 mRNA is mediated by the glucocorticoid receptor (GR). The GR antagonist, RU486, blocked the effect of the glucocorticoid dexamethasone (Dex) on MCP-1 mRNA stability in SMC culture. Using a previously reported in vitro mRNA gel shift and stability assay, antibodies to the GR blocked the ability of cytoplasmic extracts from Dex-treated SMC to decay MCP-1 mRNA. Recombinant human GR (rhGR) bound in a concentration-dependent manner to in vitro transcribed MCP-1 mRNA, whereas other members of the steroid hormone receptor family did not. Binding of GR to MCP-1 mRNA was specific as it was not found to bind other mRNAs. Immunoprecipitation of GR in extracts from Dex-treated SMC followed by real-time reverse transcription-PCR demonstrated that endogenous GR was bound specifically to MCP-1 mRNA. The addition of exogenous rhGR blocked the ability of extracts from Dex-treated SMC to degrade MCP-1 mRNA, suggesting that exogenous rhGR can compete with an endogenous GR-containing degradative complex. These data suggest a novel role for the GR in binding to and facilitating mRNA degradation. These results provide novel insights into GR function and may provide a new approach to attenuate the inflammatory response mediated by MCP-1.Monocyte chemoattractant protein-1 (MCP-1; 3 also known as CCL2) is a chemokine secreted by endothelial cells, vascular SMC, fibroblasts, and monocytes/macrophages (1). MCP-1 and its rodent analog, JE (2, 3), are not normally present in the arterial media or intima but have been found in human, primate, and rabbit atherosclerotic plaques (4 -7). In addition, MCP-1 mRNA and protein are induced within hours in the media and neointima in rat (8) and porcine (9) models of balloon arterial injury. Recent studies employing mice lacking MCP-1 or its receptor, CCR2, crossed into an atherosclerotic background (e.g. apoE Ϫ/Ϫ or LDLR Ϫ/Ϫ mice), have established that MCP-1 plays a dominant role in attracting monocyte/macrophages to developing atherosclerotic plaques (10 -12). Rupture of unstable atherosclerotic plaques, with exposure of thrombogenic material, plays a major role in acute coronary thrombotic events associated with unstable angina, myocardial infarction, and sudden death (13). In addition, MCP-1 and/or CCR2 appear to mediate intimal hyperplasia in rodent and primate models of arterial injury (14 -17). Therefore, MCP-1 appears to be an important target for attenuating arterial inflammation.Glucocorticoids are clinically important agents that possess a wide variety of anti-inflammatory and anti-proliferative properties. Glucocorticoid treatment is associated with decreased macrophage accumulation in a ...

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“…In cholesterol-fed rabbits, administration of glucocorticoid suppresses the development of atherosclerotic lesions 17 and reduces macrophage cell counts in atherosclerotic lesions. 24 These effects were partially explained by a reduction in chemotaxis of circulating monocytes.…”

Section: Discussionmentioning

confidence: 99%

“…15 Atherosclerosis is viewed as a chronic inflammatory process because one of its features is accumulation of inflammatory cells and cytokines. 1 Moreover, administration of an anti-inflammatory agent, dexamethasone, suppresses the development of atherosclerosis in various experimental animal models, including Watanabe heritable hyperlipidemic rabbits, 16 cholesterol-fed rabbits, 17 cuff-induced intimal thickening of the rabbit carotid artery, 18 and rat balloon angioplasty model. 19 The inhibitory mechanisms of dexamethasone for the development of atherosclerosis are partially explained by inhibition of smooth muscle cell migration 20 and proliferation 21 and by a reduction in chemotaxis of circulating monocytes 22 and leukocytes 23 into the subendothelial spaces.…”

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confidence: 99%

Glucocorticoid Inhibits Oxidized LDL-Induced Macrophage Growth by Suppressing the Expression of Granulocyte/Macrophage Colony-Stimulating Factor

Sakai

Biwa

Matsumura

et al. 1999

ATVB

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Abstract-Glucocorticoid, an anti-inflammatory agent, inhibits the development of atherosclerosis in various experimental animal models. This is partially explained by its ability to inhibit smooth muscle cell migration and proliferation in the intima and to reduce chemotaxis of circulating monocytes and leukocytes into the subendothelial spaces. We have recently demonstrated that oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) production plays an important role. Proliferation of cellular components is one of the characteristic events in the development and progression of atherosclerotic lesions. In the present study, we investigated the effects of glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone, and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by 85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM-CSF by macrophages, which was effectively inhibited by dexamethasone, prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone-mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage growth was significantly abrogated by RU-486, a glucocorticoid receptor antagonist. Our results suggest that the inhibitory effects of glucocorticoids on macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF production through transactivation of the glucocorticoid receptor. (Arterioscler Thromb Vasc Biol.

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Effects of Dexamethasone on Experimental Atherosclerosis in Cholesterol-fed Rabbits.

Cited by 37 publications

References 16 publications

Effect of Dexamethasone Palmitate-Low Density Lipoprotein Complex on Cholesterol Ester Accumulation in Aorta of Atherogenic Model Mice.

Effect of Dexamethasone Palmitate-Low Density Lipoprotein Complex on Cholesterol Ester Accumulation in Aorta of Atherogenic Model Mice.

A Novel Role for the Glucocorticoid Receptor in the Regulation of Monocyte Chemoattractant Protein-1 mRNA Stability

Glucocorticoid Inhibits Oxidized LDL-Induced Macrophage Growth by Suppressing the Expression of Granulocyte/Macrophage Colony-Stimulating Factor

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