Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase.
Alterations in TR [thyroid hormone (TH) receptor]1 isoform expression have been reported in models of both physiologic and pathologic cardiac hypertrophy as well as in patients with heart failure. In this report, we demonstrate that TH induces hypertrophy as a direct result of binding to the TRalpha1 isoform and, moreover, that overexpression of TRalpha1 alone is also associated with a hypertrophic phenotype, even in the absence of ligand. The mechanism of TH and TRalpha1-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor beta-activated kinase (TAK1) and p38. Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. These findings refine our previous observations on TR expression in the hypertrophied and failing heart and suggest that manipulation of thyroid hormone signaling in an isoform-specific manner may be a relevant therapeutic target for altering the pathologic myocardial program.
Kinugawa
Koichiro
K
Denver Health Medical Center, Colorado 80204, USA.
Jeong
Mark Y
MY
Bristow
Michael R
MR
Long
Carlin S
CS
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006984:Hypertrophy; D007093:Imidazoles / Q000494:pharmacology; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D020930:MAP Kinase Kinase Kinases; D020033:Protein Isoforms; D011725:Pyridines; D011988:Receptors, Thyroid Hormone; D012260:Ribonucleases; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole