Rapid nongenomic actions of thyroid hormone

Yukio Hiroi, Hyung Hwan Kim, Hao Ying, Fumihiko Furuya, Zhihong Huang, Tommaso Simoncini, Kensuke Noma, Kojiro Ueki, Ngoc Ha Nguyen, Thomas S. Scanlan, Michael A. Moskowitz, Sheue Yann Cheng, James K. Liao

Research output: Contribution to journalArticle

252 Scopus citations

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 TRα1. Treatment of endothelial cells with L-3,5,3′-triiodothyronine (T 3) increased the association of TRα1 with the p85α 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 TRα1-/-β-/- 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.

Original languageEnglish (US)
Pages (from-to)14104-14109
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number38
DOIs
StatePublished - Sep 19 2006

Keywords

  • Nitric oxide
  • Phosphatidylinositol 3-kinase
  • Protein kinase Akt
  • Stroke

ASJC Scopus subject areas

  • General

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    Hiroi, Y., Kim, H. H., Ying, H., Furuya, F., Huang, Z., Simoncini, T., Noma, K., Ueki, K., Nguyen, N. H., Scanlan, T. S., Moskowitz, M. A., Cheng, S. Y., & Liao, J. K. (2006). Rapid nongenomic actions of thyroid hormone. Proceedings of the National Academy of Sciences of the United States of America, 103(38), 14104-14109. https://doi.org/10.1073/pnas.0601600103