Regulation of Gene Expression in Cardiomyocytes by Thyroid Hormone and Thyroid Hormone Analogs 3,5-Diiodothyropropionic Acid and CGS 23425 [N-[3,5-Dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic Acid]

摘要

The heart is an important target of thyroid hormone actions.Only a limited number of cardiac target genes have been identified,and little is known about their regulation by T_3(3,3',5-triiodothyronine)and thyroid hormone analogs.We used an oligonucleotide microarray to identify novel cardiac genes regulated by T_3 and two thyroid hormone analogs,3,5-diidodothy-ropropionic acid(DITPA)and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid].DITPA binds with lower affinity than T_3 to thyroid hormone receptor alpha1 and beta1 isoforms,whereas CGS 23425 binds selectively to beta1.Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone("hy-pothyroid"control)or treated with T3,DITPA,and CGS 23425 at concentrations 5 times their respective K_d values for 48 h.The arrays were scanned and analyzed using an analysis of variance program.Sixty-four genes were identified that were>1.5 times up-or down-regulated by one of the treatments with P<0.05.The genes regulated by T_3 and DITPA were nearly identical.Thirteen genes were differentially regulated by CGS 23425.Genes encoding contractile proteins,Ca~(2+)-ATPase of sarcoplasmic reticulum and several proteins of mi-tochondrial oxidative phosphorylation,were up-regulated by T_3 and DITPA but not by CGS 23425.These results indicate that some,but not all,of the actions of thyroid hormone analogs can be explained by differences in gene activation.