Rapid Nongenomic Actions of Thyroid Hormone

The binding of thyroid hormone to the thyroid hormone receptor (TR) mediates important physiological effects. However, the transcriptional effects of TR mediated by the thyroid response element (TRE) cannot explain many actions of thyroid hormone. We postulate that TR can initiate rapid, non-TRE-mediated effects in the cardiovascular system through cross-coupling to the phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase Akt pathway. In vascular endothelial cells, the predominant TR isoform is TRα₁. Treatment of endothelial cells with L-3,5,3´-triiodothyronine (T₃) increased the association of TRα₁ with the p85α subunit of PI3kinase, leading to the phosphorylation and activation of Akt and endothelial nitric oxide synthase (eNOS). The activation of Akt and eNOS by T₃ was abolished by the PI3-kinase inhibitors, LY294002 and wortmannin, but not by the transcriptional inhibitor, actinomycin D. To determine the physiological relevance of this PI3kinase/Akt pathway, we administered T₃ to mice undergoing transient focal cerebral ischemia. Compared with vehicle, a single bolus infusion of T₃ rapidly increased Akt activity in the brain, decreased mean blood pressure, reduced cerebral infarct volume, and improved neurological deficit score. These neuroprotective effects of T₃ were greatly attenuated or absent in$eNOS^{-/-}$and$TR\alpha_{1}^{-/-}\beta^{-/-}$mice and were completely abolished in WT mice pretreated with LY294002 or a T₃ antagonist, NH-3. These findings indicate that the activation of PI3-kinase/Akt pathways can mediate some of the rapid, non-TRE effects of TR and suggest that the activation of Akt and eNOS contributes to some of the acute vasodilatory and neuroprotective effects of thyroid hormone.