Tumor necrosis factor-α inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women.
OBJECTIVE
Tumor necrosis factor (TNF)-α, a pleiotropic pro-inflammatory cytokine involved in a variety of biological processes including oxidative stress, has been associated with vascular dysfunction in aged and ovariectomized animals. We determined whether acute inhibition of TNF-α improves vascular endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women.


METHODS
Arterial stiffness (carotid artery compliance) and endothelial function (brachial artery flow-mediated dilation [FMD]) were measured in postmenopausal women (n = 23; 57 ± 1 years, mean ± SE) before and following randomization to two days of either transdermal estradiol (0.05 mg/d, N = 12) or placebo (N = 11) alone and following a single subcutaneous injection of the TNF-α inhibitor, etanercept (25 mg), and in premenopausal (n = 9; 33 ± 2 years) before and following etanercept.


CONCLUSIONS
Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than premenopausal women (P < 0.0001). In postmenopausal women, carotid artery compliance (n = 12; 0.59 ± 0.05-0.78 ± 0.06 mm(2)/mmHg × 10(-1), P < 0.001) and FMD (4.1 ± 0.6-6.0 ± 0.7%, P = 0.02) increased in response to estradiol but not placebo (n = 11). Carotid artery compliance (0.71 ± 0.06-0.81 ± 0.06 mm(2)/mmHg × 10(-1), P = 0.02) and FMD (5.2 ± 0.7-7.5 ± 0.9%, P = 0.003) increased with etanercept in the placebo group but had no effect in postmenopausal randomized to estradiol or premenopausal women. These results suggest that TNF-α contributes to impaired endothelial-dependent vasodilation and arterial stiffening in estrogen-deficient postmenopausal women.
Division of Geriatric Medicine, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: Kerrie.Moreau@UCDenver.edu.
Kerrie L
KL
Moreau
Kevin D
KD
Deane
Amie L
AL
Meditz
Wendy M
WM
Kohrt
D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001794:Blood Pressure; D001823:Body Composition; D001916:Brachial Artery / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000172:deficiency / Q000627:therapeutic use*; D004967:Estrogens / Q000172:deficiency; D000068800:Etanercept; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008875:Middle Aged; D017698:Postmenopause; D017697:Premenopause; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D059289:Vascular Stiffness / Q000187:drug effects*; D014664:Vasodilation; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004967:Estrogens; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D000068800:Etanercept
Aging; Cardiovascular disease; Endothelium; Imaging; Inflammation; Menopause