Rapid nongenomic actions of thyroid hormone

TLDR

Thyroid hormone binds the thyroid hormone receptor to mediate physiological effects, yet transcriptional TRE‑mediated actions cannot explain many of its functions, and TRα1 is the predominant receptor isoform in vascular endothelial cells. The study aims to determine whether TR can trigger rapid, non‑TRE‑mediated cardiovascular and neuroprotective effects through cross‑coupling to the PI3‑kinase/Akt signaling pathway. T3 binding to TRα1 promotes its association with the p85α subunit of PI3‑kinase, activating Akt and endothelial nitric‑oxide synthase, a process blocked by PI3‑kinase inhibitors but not by transcriptional inhibition. T3 rapidly activates Akt in the brain, lowers blood pressure, reduces cerebral infarct volume, and improves neurological outcomes, effects that are lost in eNOS‑/‑ or TRα1‑/‑beta‑/‑ mice and abolished by PI3‑kinase inhibition or a T3 antagonist, confirming PI3‑kinase/Akt mediates rapid non‑TRE actions of thyroid hormone.

Abstract

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 TRalpha1. Treatment of endothelial cells with L-3,5,3'-triiodothyronine (T3) increased the association of TRalpha1 with the p85alpha subunit of PI3-kinase, 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 PI3-kinase/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 TRalpha1-/-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.