Abstract
The endogenous thyroid hormones L-thyroxine (T4) and 3,5,3′-triiodo-L-thyronine (T3) induce angiogenesis via an endothelial cell iodothyronine receptor on integrin αVβ3. 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-T4 vs L-T3) 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-T4-agarose, L-T3, 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-T4 or L-T 4-agarose (0.01 μmol/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-T4 were blocked by the αvβ3 antagonist XT199 (0.1 μmol/ L) and by tetraiodothyroacetic acid (tetrac; 0.1 μmol/L). Tetrac inhibits binding of thyroid hormone analogs to the receptor on αvβ3 and lacks thyromimetic activity at this site; thus, the proaggregatory action of L-T4 likely involves the cell surface receptor on integrin αvβ3. 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.