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The Different Cardiac Expression of the Type 2 Iodothyronine Deiodinase Gene between Human and Rat Is Related to the Differential Response of the dio2 Genes to Nkx-2.5 and GATA-4 Transcription Factors

Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (G.F., D.S.), Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.D., M.V., G.R.), and Dipartimento di Medicina Interna (C.M.), Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy

Address all correspondence and requests for reprints to: Domenico Salvatore, M.D., Ph.D., Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Facolta di Medicina e Chirurgia, Universita degli Studi di Napoli "Federico II," 80131 Naples, Italy. E-mail: domsalva{at}unina.it.

By producing T₃ from T₄, type 2 iodothyronine deiodinase (D2) catalyzes the first step in the cascade underlying the effect exerted by thyroid hormone. Type 2 iodothyronine deiodinase mRNA is expressed at high levels in human heart but is barely detectable in the corresponding rodent tissue. Although the heart is a major target of thyroid hormone, the role of cardiac D2 and the factors that regulate its expression are unknown.

Here we report that the human Dio2 promoter is very sensitive to the cardiac transcription factors Nkx-2.5 and GATA-4. Nkx-2.5 transactivates a 6.5-kb human (h)Dio2-chloramphenicol acetyltransferase construct, with maximal induction reached with a 633-bp proximal promoter region. Interestingly, despite 73% identity with the corresponding human region, the rat Dio2 promoter is much less responsive to Nkx-2.5 induction. Using EMSA, we found that two sites in the human promoter (C and D) specifically bind Nkx-2.5. In coexpression studies, GATA-4 alone was a poor inducer of the hDio2 promoter; however in synergy with Nkx-2.5, it activated D2 reporter gene expression in the human, but not the rat promoter. Functional analysis showed that both C and D sites are required for the complete Nkx-2.5 response and for the Nkx-2.5/GATA-4 synergistic effect. In neonatal rat primary myocardiocytes, most of the hDio2-chloramphenicol acetyltransferase activity was suppressed by mutation of the Nkx-2.5 binding sites. Finally, a mutant Nkx-2.5 protein (N188K), which causes, in heterozygosity, congenital heart diseases, did not transactivate the Dio2 promoter and interfered with its activity in cardiomyocytes, possibly by titrating endogenous Nkx-2.5 protein away from the promoter.

In conclusion, this study shows that Nkx-2.5 and GATA-4 play prime roles in Dio2 gene regulation in the human heart and suggests that it is their synergistic action in humans that causes the differential expression of the cardiac Dio2 gene between humans and rats.

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