title: Differential effects of 17beta-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets.
abstract: Changes in platelet functions could contribute to thrombotic risk associated with estrogen treatments. This study was designed to test the hypothesis that three clinically relevant estrogenic treatments affect platelet function comparably. Adult female pigs were ovariectomized and randomized to either no treatment or treatment with oral 17 beta-estradiol (2 mg/day), conjugated equine estrogen (0.625 mg/day), or raloxifene (60 mg/day) for 4 wk. Platelet turnover, aggregation, and secretion were assessed before and after treatment. Platelet turnover and mRNA increased significantly only in pigs treated with 17 beta-estradiol. Expression of estrogen receptors increased with ovariectomy and decreased with all treatments. Platelet aggregation and secretion of ATP, platelet-derived growth factor, and matrix metalloproteinase-2 increased with ovariectomy. All treatments reduced both aggregation and secretion. Expression of mRNA for constitutive endothelial nitric oxide synthase (eNOS), but not eNOS protein, increased with ovariectomy. Only eNOS mRNA decreased with all treatments, but only treatment with 17 beta-estradiol increased secretion of nitric oxide from intact platelets. Platelets from 17 beta-estradiol-treated animals caused relaxation of coronary arteries, which was sensitive to inhibition of nitric oxide. Although three different estrogenic treatments reversed increases in platelet aggregation caused by ovariectomy, only 17 beta-estradiol increased platelet RNA and release of platelet-derived nitric oxide. These differences reflect transcriptional and posttranscriptional regulation of protein synthesis in bone marrow megakaryocytes and circulating platelets.
authors.affiliation: Department of Physiology and Bioengineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Muthuvel
authors.initials: M
authors.lastname: Jayachandran
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinkamp
authors.forename: Peter
authors.initials: P
authors.lastname: LaBreche
authors.forename: Margarita P
authors.initials: MP
authors.lastname: Bracamonte
authors.forename: Hiroya
authors.initials: H
authors.lastname: Okano
authors.forename: Whyte G
authors.initials: WG
authors.lastname: Owen
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Miller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D001835:Body Weight; D003331:Coronary Vessels / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D012333:RNA, Messenger / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D034421:Sus scrofa
chemical_list: D004966:Estrogens, Conjugated (USP); D006133:Growth Substances; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III