Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan This information is current as of September 23, 2021. May Abu-Taha, Cristina Rius, Carlos Hermenegildo, Inmaculada Noguera, Jose-Miguel Cerda-Nicolas, Andrew C. Issekutz, Peter J. Jose, Julio Cortijo, Esteban J. Morcillo and Maria-Jesus Sanz J Immunol 2009; 183:1393-1402; Prepublished online 24 Downloaded from June 2009; doi: 10.4049/jimmunol.0803157 http://www.jimmunol.org/content/183/2/1393 http://www.jimmunol.org/ References This article cites 47 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/183/2/1393.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! 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The Journal of Immunology Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan1 May Abu-Taha,2* Cristina Rius,2* Carlos Hermenegildo,†¶ Inmaculada Noguera,‡ Jose-Miguel Cerda-Nicolas,§# Andrew C. Issekutz,** Peter J. Jose,* Julio Cortijo,*ʈ# Esteban J. Morcillo,*¶# and Maria-Jesus Sanz3*# 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-␤-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 Downloaded from 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-1␣ 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-1␣ in 1-mo ovariectomized rats. Chronic treatment of ovariectomized http://www.jimmunol.org/ rats with low dose of 17-␤-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 inflam- mation. 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. The Journal of Immunology, 2009, 183: 1393–1402. 4 ender differences in the development of cardiovascular in postmenopausal hormone replacement therapy (HRT) both to by guest on September 23, 2021 disease are well documented in both human and animal treat postmenopausal symptoms and to reduce the risk of cardio- G studies. Cardiovascular diseases are more prevalent in vascular disease (3, 4). Estrogens reduce the serum levels of sev- men than in premenopausal women, but the incidence increases eral markers for inflammation in postmenopausal women (5). Ad- sharply in postmenopausal women (1, 2). An abundance of epide- ditionally, observational studies in ovariectomized monkeys show miological data supports a role for estrogens in this atheroprotec- that HRT inhibits coronary atherosclerosis progression by 70% if tive effect, which led to recommendations for their widespread use 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 *Department of Pharmacology, †Department of Physiology, ‡Central Research Unit, the initial treatment period (7). These discrepancies between ob- §Department of Pathology, Faculty of Medicine, ¶Clinic Hospital of Valencia Re- servational and randomized clinical trials suggest the need for re- search Foundation, and ʈResearch Foundation, University General Hospital Consor- tium, University of Valencia E.G., Valencia, Spain; #Centers for Biomedical Research search into new forms of postmenopausal HRT using a low dose of on Respiratory Diseases (CibeRes), Carlos III Health Institute, Spanish Ministry of estrogen monotherapy, which may relieve cardiovascular alter- Health, Spain; and **Department of Pediatrics, Dalhousie University, Halifax, Nova ations without causing the unwanted side effects. Scotia, Canada Estrogens influence the renin-angiotensin system, the main ef- Received for publication September 22, 2008. Accepted for publication May 18, 2009. fector peptide (i.e., angiotensin-II (Ang-II)) of which is implicated in atherogenesis beyond its hemodynamic effects (8–10). The syn- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance thesis of angiotensinogen in hepatocytes is regulated by estrogens with 18 U.S.C. Section 1734 solely to indicate this fact. (11). Plasma renin levels and angiotensin-converting enzyme 1 This study was supported by Grants SAF2005-01649, SAF2005-0669, SAF2006- (ACE) activity are significantly higher in estrogen-deficient com- 01002, SAF2008-03477, and SAF2008-03113 from Comision Interministerial de pared with estrogen-replete rats and in postmenopausal women not Ciencia y Tecnologia, Spanish Ministry of Education and Science, FIS06/0589 and Red HERACLES (Hipertensio´n Esencial: Red de Ana´lisis de Canales io´nicos de la receiving HRT compared with women on HRT (9, 12). In addition musculatura Lisa arterial y su Explotacio´n terape´utica Sistema´tica) no. RD06/0009/ to regulating the components involved in synthesizing Ang-II, 0005, Carlos III Health Institute, Spanish Ministry of Health, and research grants from Generalitat Valenciana. M.A.-T. is primarily supported by a grant from the Spanish Ministry of Foreign Affairs, C.R. by a grant from Spanish Ministry of Education and Science, and P.J.J. by a grant from the University of Valencia. 4 Abbreviations used in this paper: HRT, hormone replacement therapy; ACE, an- 2 giotensin-converting enzyme; Ang-II, angiotensin-II; CAM, cell adhesion molecule; M.A.-T. and C.R. contributed equally to this work. CINC, cytokine-induced neutrophil chemoattractant; GRO␣, growth related onco- 3 Address correspondence and reprint requests to Dr. Maria-Jesus Sanz, Departa- gene-␣; OVZ, ovariectomized. mento de Farmacología, Facultad de Medicina, Universidad de Valencia, Avenida Blasco Iban˜ez, 15, E-46010 Valencia, Spain. E-mail address: [email protected] Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803157 1394 MENOPAUSE CAUSES MODERATE SYSTEMIC INFLAMMATION estrogens also alter the expression of Ang-II AT1 receptors in Table I. Clinical characteristics of the pre and postmenopausal women many target tissues (10, 13). Using intravital microscopy to di- rectly observe kinetic events in the rat mesenteric microcirculation, Postmenopausal Premenopausal a we found that acute (90 min) blockade of estrogen receptors in Variable Women Women male rats induces leukocyte-endothelial cell interactions in the Number 13 6 postcapillary venules, and these inflammatory responses are sig- Smokers No No nificantly attenuated by an AT receptor antagonist (14). Later, we Age (years) 56.3 Ϯ 2.4 25.8 Ϯ 0.9 1 Ϯ demonstrated that exposure to Ang-II in vivo induces arteriolar Years of menopause 10.6 2.4 Weight (kg) 71.2 Ϯ 4.5 54.1 Ϯ 0.5 mononuclear cell adhesion (15). Circulating leukocytes (cells/␮l) 6485.7 Ϯ 407.1 7117 Ϯ 654 Experimental studies have demonstrated that leukocyte adhe- Glucose (g/L) 95.3 Ϯ 1.7 86.7 Ϯ 1.4 sion and infiltration into the arterial wall, regulated by leukocyte Total cholesterol (g/L) 240.5 Ϯ 8.1 192.0 Ϯ 8.7 and endothelial cell adhesion molecules (CAMs) and chemokines, Triglycerides (g/L) 77.5 Ϯ 7.7 62.7 Ϯ 4.9 Ϯ Ϯ represent an essential step in atherosclerotic lesion formation (16– HDL cholesterol (g/L) 75.0 3.6 70.5 5.2 LDL cholesterol (g/L) 147.8 Ϯ 8.5 109.0 Ϯ 5.4 20). Estrogens are associated with improved endothelial function, FSH (mIU/ml) 77.6 Ϯ 9.7 4.0 Ϯ 0.7 by elevation of NO and prostacyclin levels, enhanced vasodilata- LH (mIU/ml) 30.1 Ϯ 4.7 5.8 Ϯ 1.3 tion, inhibition of vascular smooth muscle cell proliferation, and Estradiol (pg/ml) 13.5 Ϯ 1.5 164.3 Ϯ 5.3 Ϯ Ϯ reduction of platelet aggregation, and they are therefore thought to MABP (mmHg) 101.3 3.8 84.4 3.4 attenuate atherosclerosis (4). In the present study, we have used a HDL indicates high density lipoprotein; LDL, low density lipoprotein; FSH, whole blood from both healthy premenopausal and postmeno- follicle-stimulating hormone; LH, luteinizing hormone; MABP, mean arterial blood Downloaded from pressure.