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]

Abstract

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-diidodothyropropionic 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 ("hypothyroid" control) or treated with T(3), 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 mitochondrial 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.