Loss of estrogen receptor beta decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice.
Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (betaER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22-24 months) WT and estrogen receptor beta knockout (betaERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17beta-estradiol were comparable between WT and betaERKO mice. Number of spontaneous deaths was greater in the betaERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc ( 1 ) complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from betaERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in betaERKO compared to WT mice. These results suggest that deficiencies in betaER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females.
Jayachandran
Muthuvel
M
Department of Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA, jaya.m@mayo.edu.
Preston
Claudia C
CC
Hunter
Larry W
LW
Jahangir
Arshad
A
Owen
Whyte G
WG
Korach
Kenneth S
KS
Miller
Virginia M
VM
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001835:Body Weight; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000097:blood; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005640:Follicle Stimulating Hormone / Q000097:blood; D007773:Lactates / Q000097:blood; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009929:Organ Size; D010100:Oxygen / Q000378:metabolism; D010974:Platelet Aggregation
D047629:Estrogen Receptor beta; D007773:Lactates; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III; D010100:Oxygen