COX-2-derived prostacyclin confers atheroprotection on female mice.
Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin, PGI2, by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PGI2 receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females.
Egan
Karine M
KM
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, PA 19104, USA.
Lawson
John A
JA
Fries
Susanne
S
Koller
Beverley
B
Rader
Daniel J
DJ
Smyth
Emer M
EM
Fitzgerald
Garret A
GA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002318:Cardiovascular Diseases / Q000139:chemically induced; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress; D015539:Platelet Activation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D012727:Sex Characteristics; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology
D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D007783:Lactones; D044006:Receptors, Epoprostenol; D011973:Receptors, LDL; D013450:Sulfones; C116926:rofecoxib; D004958:Estradiol; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases