Estrogen, inflammation and cardiovascular risk in women: a critical appraisal

Störk, Stefan; Schouw, Yvonne T. van der; Grobbee, Diederick E.; Bots, Michiel L.

doi:10.1016/j.tem.2004.01.005

Cited by 57 publications

(37 citation statements)

References 115 publications

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“…In addition, it has been shown that estradiol has pro-inflammatory properties in cultured microglia derived from aging females, while it has no significant effects in microglia derived from young females (Johnson and Sohrabji, 2005). Furthermore, the potential pro-inflammatory effects of estradiol have been proposed to contribute to the failure of clinical trials to prove the benefits of hormone replacement therapies (Bushnell, 2005;Stork et al, 2004). Thus, steroid hormones should be defined as immuno-modulatory agents, exerting permissive, stimulatory, or blocking effects depending on hormone concentration, endpoints measured, cell types studied, and inflammation models used, as observed for glucocorticoids (Dinkel et al, 2002;Sternberg, 2001;Yeager et al, 2004).…”

Section: Estrogen Receptors In Microgliamentioning

confidence: 99%

Steroid hormone receptor expression and function in microglia

Sierra

Gottfried-Blackmore

Milner

et al. 2008

Glia

355

238

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Steroid hormones such as glucocorticoids and estrogens are well-known regulators of peripheral immune responses and also show anti-inflammatory properties in the brain. However, the expression of steroid hormone receptors in microglia, the pivotal immune cell that coordinates the brain inflammatory response, is still controversial. Here we use real time RT-PCR to show that microglia, isolated from adult fms-EGFP mice by FACS, express glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and estrogen receptor alpha (ERa). GR was the most abundant steroid hormone receptor transcript in microglia. The presence of GR and ERa immunoreactivity was further confirmed in vivo at the ultrastructural level. To understand the role of steroid hormone receptors during the inflammation process, we evaluated the expression of steroid hormone receptors after inflammatory challenge and found a significant down-regulation of GR, MR, and ERa in microglia. Finally, we tested the immunomodulatory properties of estrogens and glucocorticoids. Estradiol benzoate did not have any significant impact on the inflammatory profile of ex vivo sorted microglia, either in resting conditions or after challenge. Furthermore, corticosterone was a more consistent anti-inflammatory agent than 17b-estradiol in vitro. Our results support the hypothesis that adult microglia are a direct target of steroid hormones and that glucocorticoids, through the predominant expression of GR and MR, are the primary steroid hormone regulators of microglial inflammatory activity. The down-regulation of steroid hormone receptors after LPS challenge may serve as a prerequisite to suppressing the antiinflammatory actions of endogenous steroid hormones on the immune system, and contribute to a sustained activation of microglia. V V C

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Section: Estrogen Receptors In Microgliamentioning

confidence: 99%

Steroid hormone receptor expression and function in microglia

Sierra

Gottfried-Blackmore

Milner

et al. 2008

Glia

355

238

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“…Loss of the cardiovascular protective effect that occurs around menopause corresponds with the decline of ovarian function, suggesting that ovarian hormone deficiency may play a critical role in the CVD development (3,4).…”

Section: Introductionmentioning

confidence: 99%

Estrogen is a modulator of vascular inflammation

2008

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SummaryVascular inflammation underlies the pathogenesis of atherosclerosis. Atherosclerotic changes in the vasculature lead to conditions such as coronary artery disease and stroke, which are the major causes of morbidity and mortality worldwide. Epidemiological studies in premenopausal women suggest a beneficial role for estrogen in preventing vascular inflammation and consequent atherosclerosis. However, the benefits of estrogen are absent or even reversed in older postmenopausal subjects. The modulation of inflammation by estrogen under different conditions might explain this discrepancy. Estrogen exerts its antiinflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system. On the other hand, estrogen also elicits proinflammatory changes under certain conditions, which are less completely understood. Some of the mechanisms underlying a possible proinflammatory role for estrogen include increased expression of the proinflammatory receptor for advanced glycation end products, increased tyrosine nitration of cellular proteins, and generation of reactive oxygen species through an uncoupled eNOS. In this review, we have presented evidence for both antiinflammatory and proinflammatory pathways modulated by estrogen and how interactions among such pathways might determine the effects of estrogen on the vascular system. IUBMBIUBMB Life, 60(6): 376-382, 2008

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“…Estrogens reduce the serum levels of several markers for inflammation in postmenopausal women (5). Additionally, observational studies in ovariectomized monkeys show that HRT inhibits coronary atherosclerosis progression by 70% if begun early after ovariectomy (6). However, some clinical trials have failed to demonstrate cardiovascular beneficial effects of HRT and have even suggested increased cardiovascular risk during the initial treatment period (7).…”

mentioning

confidence: 99%

Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan

Abu-Taha¹,

Rius²,

Hermenegildo

et al. 2009

The Journal of Immunology

142

102

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The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-β-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1α and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1α in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-β-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.

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Estrogen, inflammation and cardiovascular risk in women: a critical appraisal

Cited by 57 publications

References 115 publications

Steroid hormone receptor expression and function in microglia

Steroid hormone receptor expression and function in microglia

Estrogen is a modulator of vascular inflammation

Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan

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