Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy

Physiological and pathological cardiac hypertrophy have directionally oppos ite changes in transcription of thyroid hormone (TH)-responsive genes, incl uding alpha- and beta -myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. Thes e findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH rec eptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological ra t cardiac hypertrophy models with hypothyroid- and hyperthyroid-like change s in the TH target genes, alpha- and beta -MyHC and SERCA. All 3 TR subtype s in myocytes were downregulated in 2 hypertrophy models with a hypothyroid -like mRNA phenotype, phenylephrine in culture and pressure overload in viv o. Myocyte TR beta1 was upregulated in models with a hyperthyroid-like phen otype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocy te culture, TR overexpression, or excess T3, reversed the effects of phenyl ephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfectio n and treatment with the TR beta1-selective agonist GC-1 suggested differen t functional coupling of the TR isoforms, TR beta1 to transcription of beta -MyHC, SERCA, and TR beta1, and TR alpha1 to alpha -MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulat ion and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological an d pathological cardiac hypertrophy.