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]

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, Ca2+-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.