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 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.
Hiroi
Yukio
Y
Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
Kim
Hyung-Hwan
HH
Ying
Hao
H
Furuya
Fumihiko
F
Huang
Zhihong
Z
Simoncini
Tommaso
T
Noma
Kensuke
K
Ueki
Kojiro
K
Nguyen
Ngoc-Ha
NH
Scanlan
Thomas S
TS
Moskowitz
Michael A
MA
Cheng
Sheue-Yann
SY
Liao
James K
JK
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D018696:Neuroprotective Agents; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt