Raloxifene, a Selective Estrogen Receptor Modulator, Reduces Carrageenan-Induced Acute Inflammation in Normal and Ovariectomized Rats

Esposito, Emanuela; Iacono, A; Raso, Giuseppina Mattace; Pacilio, Maria; Coppola, Anna; Carlo, R. Di; Meli, Rosaria

doi:10.1210/en.2005-0375

Cited by 42 publications

(37 citation statements)

References 43 publications

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“…Therefore, short-term nongenomic effects of raloxifene as discussed above may be associated with long-term genomic effects in the vessel wall. On testing this hypothesis, we detected novel anti-inflammatory properties of raloxifene in isolated vascular SMCs in culture, consistent with those shown in microglial cells (Suuronen et al, 2005) and on carrageenan-induced paw edema and pleurisy after in vivo treatment (Esposito et al, 2005). In addition, the present study reports that the rapid vasorelaxation mediated by raloxifene was retained in aortic tissues from rats under moderate inflammatory challenge as induced by low-dose LPS.…”

Section: Discussionsupporting

confidence: 86%

“…The reported decrease in inflammatory responses after raloxifene treatment in vitro and in vivo (Esposito et al, 2005;Suuronen et al, 2005) led us to test potential antiinflammatory effects of the drug in the vessel wall. Therefore, the effect of raloxifene on vascular tone was investigated in ex vivo aorta from rats under inflammatory challenge.…”

Section: Resultsmentioning

confidence: 99%

“…So far, there is no information as to the involvement of specific ER isoforms in the vascular effects of raloxifene. Beyond the modulation of vascular tone, there have been recent indications that raloxifene is capable of decreasing acute inflammation induced by lipopolysaccharide (LPS) in microglial cells (Suuronen et al, 2005) and by carrageenan in normal and ovariectomized rats (Esposito et al, 2005), but the relevance of these findings to the cardiovascular system is at present unknown.…”

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confidence: 99%

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Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Pinna

Bolego

Sanvito

et al. 2006

J Pharmacol Exp Ther

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Previous studies reported the ability of raloxifene to acutely relax arterial and venous vessels, but the underlying mechanisms are controversial. Anti-inflammatory effects of the drug have been reported in nonvascular tissues. Therefore, the aim of this study was to investigate the nature of short-and longterm effects of raloxifene on selected aspects of vascular function in rat aorta. Isometric tension changes in response to raloxifene were recorded in aortic rings from ovariectomized female rats that underwent estrogen replacement, whereas long-term experiments were performed in isolated aortic smooth muscle cells (SMCs). Raloxifene (0.1 pM-0.1 M) induced acute vasorelaxation through endothelium-and nitric oxide (NO)-dependent, prostanoid-independent mechanisms. The relaxant response to raloxifene was significantly weaker than that to 17␤-estradiol and was sensitive to neither the nonselective estrogen receptor antagonist ICI 182,780 [7,4,5,5,sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol] nor a selective estrogen receptor (ER) ␣ antagonist. This rapid vasorelaxant effect was retained in aortic rings from rats treated with 0.1 mg/kg, but not 1 mg/kg, lipopolysaccharide, 4 h before sacrifice. In cultured aortic SMCs, raloxifene treatment (1 nM-1 M) for 24 h reduced inducible NO synthase activation in response to cytokines. This effect was prevented by the selective ER␣ antagonist and was associated with upregulation of ER␣ protein levels, which dropped markedly upon cytokine stimulation. These findings illustrate the relevance of classic ER-dependent pathways to the vascular anti-inflammatory effects rather than to the nongenomic vasorelaxation induced by raloxifene and may assist in the design of novel ER isoform-selective estrogen-receptor modulators targeted to the vascular system.Raloxifene is a selective estrogen-receptor modulator (SERM) approved for use in osteoporosis and has been suggested to be cardioprotective in women at high risk for coronary heart disease (Barrett-Connor et al., 2002), although these results were from post hoc analyses. In fact, the results of the recently completed RUTH (Raloxifene Use for The Heart) study indicate that treatment with raloxifene does not significantly affect the risk of coronary events in postmenopausal women at risk for coronary disease (Barrett-Connor et al., 2006). Thus, a more detailed understanding of raloxifene pharmacological action in vascular tissues is required to better define and unravel potential benefits of treatment with raloxifene and other SERMs.A certain number of studies have examined the direct effects of raloxifene on the vessel wall. It has been consistently shown that the drug acutely relaxes different arterial (Figtree et al., 1999;Tsang et al., 2004;Chan et al., 2005;Leung et al., 2005) and venous (Bracamonte et al., 2002;Chan et al., 2005) vessels from different animal species. A variety of underlying mechanisms, however, can be involved, including enhanced endothelial NO production (Figtree et al., 1999;Bracamonte et al., 200...

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Pinna

Bolego

Sanvito

et al. 2006

J Pharmacol Exp Ther

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“…The mechanism responsible for the anti-inflammatory activity of estradiol systemic administration may be due to the hormone-dependent blockade of cytokine production, such as IL-1 and TNF-␣. Moreover, the anti-inflammatory effect of acute administration of E 2 (50 g/kg) on carrageenan paw edema of male rats was also shown (Esposito et al, 2005). Estrogens might also inhibit macrophage infiltration in the damaged tissues.…”

Section: Discussionmentioning

confidence: 86%

PPAR-α Contributes to the Anti-Inflammatory Activity of 17β-Estradiol

Crisafulli¹,

Bruscoli²,

Esposito³

et al. 2009

J Pharmacol Exp Ther

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Because studies have shown that 17␤-estradiol (E2) produces anti-inflammatory effects after various adverse circulatory conditions, we have recently demonstrated that E2 significantly reduced the acute lung injury. Moreover, previous results suggest that peroxisome proliferator-activated receptor-␣ (PPAR-␣), an intracellular transcription factor activated by fatty acids, plays a role in the control of inflammation. With the aim to characterize the role of PPAR-␣ in estrogen-mediated anti-inflammatory activity, we tested the efficacy of E2 in an experimental model of lung inflammation, carrageenan-induced pleurisy, comparing ovariectomized wild-type (WT) and PPAR-␣ lacking (PPAR-␣KO) mice. Results indicate that E2-mediated anti-inflammatory activity is weakened in PPAR-␣KO mice, compared with WT control groups. In particular, E2 was less effective in PPAR-␣KO, compared with WT mice, in inhibition of cell migration as well as lung injury, NF-kB activation, TNF-␣ production, and inducible nitric-oxide synthase (iNOS) activation. Moreover, macrophages from PPAR-␣KO were less susceptible to E2-induced iNOS inhibition in vitro compared with macrophages from WT mice. Moreover, the results indicate that PPAR-␣ was required for estrogen receptor up-regulation, following E2 treatment. These results show for the first time that PPAR-␣ contributes to the anti-inflammatory activity of E2.

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“…One previous study was able to demonstrate the antiinflammatory properties of raloxifene in carrageenan-induced acute inflammation in rats (29). Another SERM, idoxifene, was found to be efficient, in both prophylactic and therapeutic treatment strategies, in adjuvant-induced arthritis in rats, with less paw inflammation, lower serum levels of IL-6, and improved BMD (30).…”

Section: Discussionmentioning

confidence: 98%

Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis

Jochéms

Islander

Kallkopf

et al. 2007

Arthritis & Rheumatism

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Objective. In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis.Methods. Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction.Results. Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor ␣ and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM.Conclusion. In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.

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Raloxifene, a Selective Estrogen Receptor Modulator, Reduces Carrageenan-Induced Acute Inflammation in Normal and Ovariectomized Rats

Cited by 42 publications

References 43 publications

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

PPAR-α Contributes to the Anti-Inflammatory Activity of 17β-Estradiol

Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis

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