• Skip to primary navigation
  • Skip to main content
  • Skip to primary sidebar
  • Skip to footer

Johns Hopkins Arthritis Center

Show Search
Hide Search
  • Disease Information
    • Rheumatoid Arthritis
    • Psoriatic Arthritis
    • Ankylosing Spondylitis
    • Osteoarthritis
    • Gout
    • Osteoporosis
  • Patient Corner
    • Drug Information Sheets
    • Managing Your Arthritis
    • RheumTV – Patient Education Video Library
  • Our Research
    • Patient-Centered Outcomes Research
    • Current Research Studies
    • The Camille Julia Morgan Arthritis Research and Education Fund
  • About Us
    • Appointment Information
    • Contact Us
    • Our Faculty
    • Our Staff
    • Rheumatology Specialty Centers
  • Donate
Home / Arthritis News / Association Between Estrogen and COX-2 in Protection from Atherosclerosis

Association Between Estrogen and COX-2 in Protection from Atherosclerosis

April 13, 2005 By Arthritis Center

Prostacyclin, a pleotropic prostaglandin with multiple atheroprotective effects, is produced from arachidonic acid via the catalytic activity of cyclooxygenase-2 (COX-2). Estrogen is known to increase COX-2 expression in vascular endothelial cells. Here, Egan et al (Science 306:1954, 2004) examine the putative effects of estrogen on the regulation of COX-2 and subsequent production of atheroprotective prostacyclin.

Methods and Results:

LDL receptor knock-out (LDLR KO) mice, a strain known to exhibit an increased burden of atherosclerosis compared to wild-type mice, were studied. Male LDLR KO mice exhibited a greater extent of aortic atherosclerosis at 3 and 6 months of age than female LDLR KO mice. However, female LDLR KO mice lacking the prostacyclin receptor developed significantly greater aortic atherosclerosis compared to female LDLR KO mice with intact prostacyclin receptors. This effect was not observed in male LDLR KO mice lacking the prostacyclin receptor.

Male and female LDLR KO mice lacking prostacyclin receptors exhibited increased platelet activation (measured by the level of urinary excretion of a metabolite of thromboxane), and oxidative stress (measured by the level of urinary excretion of isoprostanes, reflecting lipid peroxidation) compared to LDLR KO mice with functioning prostacyclin receptors.

Cultured mouse aortic smooth muscle cells (MASMCs) exposed to oxidative stress (via H2O2) demonstrated increased prostacyclin synthesis, lipid peroxidation, and production of reactive oxygen species. COX-2 expression was not affected by oxidative stress. MASMCs lacking prostacyclin receptors demonstrated comparatively greater levels of lipid peroxidation and production of reactive oxygen species. Addition of a prostacyclin receptor agonist attenuated lipid peroxidation and production of reactive oxygen species in MASMCs exposed to oxidative stress, all suggesting a role for prostacyclin receptors in mediating the response of aortic smooth muscle cells to oxidative stress. Long-term exposure of MASMCs to estrogen resulted in increased production of COX-2 and prostacyclin, and an attenuated response to oxidative stress. This effect was found to be mediated through estrogen receptor.

Treatment of ovariectomized LDLR KO and wild-type mice with estrogen resulted in increased prostacyclin synthesis and decreased lipid peroxidation. Ovariectomized LDLR KO mice lacking prostacyclin receptors demonstrated increased aortic atherosclerosis compared to LDLR KO mice with functioning prostacyclin receptors. Treatment with estrogen reduced aortic atherosclerosis by 80% in LDLR KO mice with functioning prostacyclin receptors, but only by 32% in LDLR KO mice lacking prostacyclin receptors.

Conclusions:

Atheroprotective effects of prostacyclin in female mice are mediated, at least in part, through estrogen induced upregulation of COX-2.

Editorial Comment:

This well designed series of in vitro and in vivo experiments illustrates an important novel association between estrogen and COX-2 in protection from atherosclerosis. In this context, states leading to reduced activity of either COX-2 (via selective inhibition with COX-2 inhibitors) or estrogen (via menopause) might be expected to confer an increased susceptibility to atherosclerosis. In addition, these results suggest that chronic COX-2 inhibition in pre-menopausal women may serve to cancel out or reduce the atheroprotective effects of estrogen in younger women. Though this relationship has not been confirmed in humans, recent high profile evidence of increased cardiovascular events associated with several commercially available COX-2 inhibitors is compelling, though sub-analyses by gender and hormone status have not been made public to date. However, humans are complex, and many pro- and anti-atherogenic mechanisms are likely at play. To add additional complexity, some mediators may play both pro- and anti-atherogenic roles, depending on the context. An example is particularly pertinent in the discussion of the present investigation: Though estrogen would appear to play an unequivocally anti-atherogenic role based on the model presented, evidence from several large epidemiologic studies in women (HERS II and the Womens Health Initiative) have identified no role for estrogen replacement therapy for the primary or secondary prevention of atherosclerosis. In some circumstances, estrogen replacement was associated with a greater risk of cardiac events, perhaps through the promotion of a pro-thrombotic state. As always, extrapolation of data from animal studies requires a certain level of caution. However, a fresh look at the HERS II and Womens Health Initiative data considering concomitant COX-2 inhibitor use might yield evidence to sway opinion on this subject.

Receive the Latest News from Johns Hopkins Rheumatology

Receive the Latest News from Johns Hopkins Rheumatology

Join our mailing list to receive the latest news and updates from Johns Hopkins Rheumatology.

Interested In

You have Successfully Subscribed!

Arthritis Center

Founded in 1998, the Arthritis Center at Johns Hopkins is dedicated to providing quality education to patients and healthcare providers alike.

Use of this Site

All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.

Primary Sidebar

Recent News

Exercise Tips for Arthritis Patients

How Does Exercise Affect my Joints? How Frequently Should I Be Exercising? Should I Lose Weight for Exercise to be

Risks and Benefits of Biologic Medications

Victoria Ruffing, RN, BC, Director of Patient Education at the Johns Hopkins Arthritis Center, shares the risks and benefits of biologic for

How to Manage Rheumatoid Arthritis Flares

Through research, doctors have a clearer understanding of how flares can impact a patient on a personal and emotional level. Dr. Uzma Haque

Complementary & Alternative Medicines for Psoriatic Arthritis

There are many complementary & alternative medicines and practices that have been found to be beneficial in curbing arthritis pain,

I can’t be a runner because I have Rheumatoid Arthritis (RA), right?

Dr. Manno discusses running and Rheumatoid Arthritis. Is it an option for the RA patient?

News Categories

  • Ankylosing Spondylitis News
  • Fibromyalgia News
  • Gout News
  • Lupus News
  • Osteoarthritis News
  • Osteoporosis News
  • Psoriatic Arthritis News
  • Rheumatoid Arthritis News
RheumTV Logo

Rheum.TV is an informational platform created to educate patients living with a rheumatic disease. With over 100 disease education videos produced by the team at Johns Hopkins Rheumatology.

Visit Rheum.TV

Footer

Johns Hopkins Rheumatology

  • Johns Hopkins Rheumatology
  • Johns Hopkins Lupus Center
  • Johns Hopkins Lyme Disease Research Center
  • Johns Hopkins Myositis Center
  • Johns Hopkins Scleroderma Center
  • Johns Hopkins Sjögren’s Syndrome Center
  • Johns Hopkins Vasculitis Center

Connect With Us

  • Facebook
  • Twitter
  • YouTube

Johns Hopkins Medicine

© 2023 Johns Hopkins Arthritis Center
Patient Privacy