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 T₃ (3,3′,5-triiodothyronine) and thyroid hormone analogs. We used an oligonucleotide microarray to identify novel cardiac genes regulated by T₃ 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 T₃ to thyroid hormone receptor α1 and β1 isoforms, whereas CGS 23425 binds selectively to β1. Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone ("hypothyroid" 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 T₃ 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 T₃ 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.