Estrogen regulation of tumor necrosis factor-alpha: a missing link between menopause and cardiovascular risk in women?

Over the past decade, inflammation has been gaining widespread attention among scientists because of accumulating evidence implicating inflammation as an important mediator in the progression of cardiovascular disease (CVD). Clinical and experimental studies have shown strong associations between the risk for CVD and several inflammatory markers. In the majority of conditions that are high risk factors for CVD (eg, hypercholesterolemia, hypertension, and diabetes), the vascular system or, more specifically, the vascular endothelium, elicits an inflammatory response that could lead to increased oxidative stress as well as to other processes that contribute to vascular damage.1 This theory has also been supported by the fact that the most common drugs used for the treatment of CVD—statins, aspirin, angiotensin II inhibitors, and PPAR agonists—all have anti-inflammatory effects. Among the proinflammatory molecules, tumor necrosis factor(TNF) has been identified as an important mediator of vascular dysfunction through its ability to decrease the expression of endothelial nitric oxide synthase (eNOS)2 and, concomitantly, to induce NAD(P)H oxidase activity.3 Moreover, high levels of TNFin the systemic circulation have been detected in conditions that present significant risk for CVD such as hypertension and diabetes.4 In this issue, Arenas et al5 demonstrate a new role of TNFin the development of vascular dysfunction in what can be considered another risk factor for CVD, ie, estrogen deficiency. Although heated controversy exists over the value of estrogen replacement therapy in protecting against cardiovascular disease, many animal and clinical studies have shown that estrogen has direct beneficial effects on the cardiovascular system. Estrogen exhibits favorable effects on endothelial function. Estrogen deficiency, as a consequence of menopause or ovariectomy, decreases endotheliumdependent relaxation in women and in animal models, thereby potentially contributing to increased vasoconstrictor mechanisms that lead to increased blood pressure. This negative effect of estrogen deficiency is reversed by estrogen replacement. The positive vascular effects of estrogen have been attributed primarily to estrogen upregulation of endothelium-derived nitric oxide (NO).6 Probable mechanisms involved in estradiol-induced increases in NO production include: (1) transcriptional stimulation of eNOS gene expression; (2) nongenomic activation of eNOS enzyme activity via a PI3-kinase/Akt-mediated signaling pathway; and (3) a decrease in NO catabolism via reduced superoxide anion (O2 )-mediated conversion of NO to peroxynitrite. Induction of eNOS transcription by estrogen has been demonstrated in a variety of tissues, which is consistent with the presence of estrogen response elements in the eNOS promoter.7 In addition to the increase in eNOS expression, estrogen causes rapid amplification of eNOS activity by directly activating the PI3-kinase/Akt pathway resulting from the interactions between the estrogen receptor and the regulatory subunit of PI3-kinase.8 Furthermore, the protective effects of estrogen have also been attributed to an increase in the NO/O2 ratio in the vessel wall, thereby resulting in increased bioavailability of NO. A recent study has shown that estrogen reduces O2 bioavailability in rat microvessels in vivo,9 and in human umbilical vein cultured endothelial cells, 17 -estradiol decreases expression of the NAD(P)H oxidase subunit, gp91phox, and upregulates eNOS expression, thereby improving the NO/O2 balance.10 Estrogen-mediated anti-inflammatory effects have also been proposed to contribute to cardiovascular protection. The onset of menopause has been associated with spontaneous increases in cytokine production, specifically, TNFand the interleukins, IL-1 and IL-6. Moreover, cytokine levels are reportedly lower in postmenopausal women on hormone replacement therapy and in estrogen-treated ovariectomized mice compared with untreated controls.11 Estrogen treatment in vitro inhibits the release of proinflammatory cytokines in a variety of cell types, such as monocytes, osteoblasts, and endothelial cells. Estrogen deficiency has also been shown to enhance the sensitivity of those cells to these cytokines by upregulating cytokine receptor expression.11 Despite the increasing evidence demonstrating the anti-inflammatory effects of estrogen, before now there has been no evidence clearly linking cardiovascular damage to the upregulation of pro-inflammatory cytokines that occurs during estrogen deficiency. In this issue of Hypertension, Arenas et al5 report a novel mechanism for estrogen action in the vasculature and provide data demonstrating an important link between inflammation and cardiovascular risk in the menopausal female. Circulating levels of the proinflammatory cytokine TNFwere found to be 7-fold greater in ovariectomized rats compared with estrogen-replaced ovariectomized animals or intact cycling animals. The elevated levels of TNFafter estrogen defiThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington DC. Correspondence to Kathryn Sandberg, PhD, Director, Center for the Study of Sex Differences in Health, Aging and Disease; Professor of Medicine and Physiology at Georgetown University. Suite 232 Building D, 4000 Reservoir Road, NW. Washington, DC 20057. E-mail [email protected] (Hypertension. 2005;46:21-22.) © 2005 American Heart Association, Inc.