title: Human platelet aggregation and degranulation is induced in vitro by L-thyroxine, but not by 3,5,3'-triiodo-L-thyronine or diiodothyropropionic acid (DITPA).
abstract: The endogenous thyroid hormones L-thyroxine (T(4)) and 3,5,3'-triiodo-L-thyronine (T(3)) induce angiogenesis via an endothelial cell iodothyronine receptor on integrin alphaVbeta3. This receptor also exists on platelets. Diiodothyropropionic acid (DITPA) and GC-1, a noniodinated thyroid hormone analog, also induce angiogenesis. Here we examined the effects of iodothyronines (L-T(4) vs L-T(3)) and analogs DITPA and GC-1 on human platelet function. Subthreshold aggregation of platelets obtained from healthy human donors was induced with collagen. Platelet activation (proaggregation) and adenosine triphosphate (ATP) secretion (degranulation) induced by L-T( 4), L-T(4)-agarose, L-T(3), DITPA, or GC-1 were determined simultaneously. Platelet aggregation and ATP secretion induced by a subthreshold level of collagen were enhanced 3-fold by either L-T(4) or L-T( 4)-agarose (0.01 micromol/L) as compared to control, whereas, L-T( 3), DITPA, or GC-1 had no effect under the same conditions. The platelet proaggregatory and degranulation effects of L-T(4) were blocked by the alphavbeta3 antagonist XT199 (0.1 micromol/ L) and by tetraiodothyroacetic acid (tetrac; 0.1 micromol/L). Tetrac inhibits binding of thyroid hormone analogs to the receptor on alphavbeta3 and lacks thyromimetic activity at this site; thus, the proaggregatory action of L-T(4) likely involves the cell surface receptor on integrin alphavbeta3. The thyroid hormone receptor (TR) on human platelets but not endothelial cells distinguishes among iodothyronines, reflecting quantitative differences in integrin sites on endothelial cells and platelets or qualitative differences in the phospholipids/protein microenvironment of endothelial and platelet membranes that can affect integrin function. Additional studies in different populations with larger sample sizes are warranted to determine the impact of the current findings on clinical interventions.
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York 12144, USA. shaker.mousa@acphs.edu
authors.forename: Shaymaa S
authors.initials: SS
authors.lastname: Mousa
authors.forename: Faith B
authors.initials: FB
authors.lastname: Davis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000293:Adolescent; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003094:Collagen / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004104:Diiodothyronines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D010636:Phenols / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects*; D013379:Substrate Specificity; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C426703:3-(3-(3-(4,5-dihydroimidazol-2-ylamino)propyloxylisoxazol-5-yl)carbonylamino)-2-(phenylsulfonylamino)propionic acid; D000085:Acetates; D004104:Diiodothyronines; C413355:GC 1 compound; D007093:Imidazoles; D010636:Phenols; D011422:Propionates; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; C082182:3,5-diiodothyropropionic acid; D000255:Adenosine Triphosphate; D003094:Collagen; C011126:tetraiodothyroacetic acid; D013974:Thyroxine