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Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis
K Ojamaa1, A M Samarel, J M Kupfer
1Department of Medicine, North Shore University Hospital, Manhasset, New York 11030.
Insights
Thyroid hormone (T4) requires hemodynamic load for cardiac growth. However, T4 directly influences cardiac gene expression, altering specific genes like myosin heavy chain (MHC) and SR Ca(2+)-ATPase, independent of growth.
Area of Science:
- Cardiology
- Molecular Biology
- Endocrinology
Background:
- Thyroid hormone (T4) is known to induce cardiac hypertrophy.
- Hemodynamic loading plays a crucial role in mediating T4-induced cardiac growth.
- Direct cellular effects of T4 on cardiac gene expression are suspected.
Purpose of the Study:
- To investigate the direct effects of T4 on cardiac gene expression independent of hemodynamic load.
- To determine if T4 can stimulate cardiac protein synthesis without increased hemodynamic stress.
- To analyze the impact of T4 on specific cardiac genes, including myosin heavy chain (MHC) and SR Ca(2+)-ATPase.
Main Methods:
- Administration of T4 to hemodynamically unloaded heterotopic isografts for 72 hours.
- Measurement of total cardiac protein and MHC synthetic rates in isografts and in situ working hearts.
- Quantification of total left ventricle RNA, alpha-MHC, beta-MHC, and SR Ca(2+)-ATPase mRNA concentrations.
Main Results:
- T4 did not stimulate cardiac growth in the hemodynamically unloaded isograft.
- Protein and MHC synthesis rates were significantly lower in the T4-treated isograft compared to the in situ heart.
- T4 increased alpha-MHC and SR Ca(2+)-ATPase mRNA by 181% and 208%, respectively, and abolished beta-MHC expression, despite unchanged total RNA content.
Conclusions:
- Thyroid hormone (T4) requires increased hemodynamic load to stimulate cardiac protein synthesis.
- T4 can directly alter the expression of specific cardiac genes, such as alpha-MHC and SR Ca(2+)-ATPase, independent of cardiac growth.
- Some phenotypic changes observed with thyroid hormone treatment result from direct effects on cardiac genes, not solely from growth-related mechanisms.
Abstract:
Prior studies have demonstrated the importance of hemodynamic loading in mediating thyroxine (T4)-induced cardiac hypertrophy. Direct cellular effects of thyroid hormone have been implicated in modulating the expression of the myosin heavy chain (MHC) genes and the slow sarcoplasmic reticulum calcium adenosine triphosphatase (SR Ca(2+)-ATPase) gene. In the present report, administration of T4 for 72 h did not stimulate growth of the hemodynamically unloaded heterotopic isograft. The synthetic rates of total cardiac proteins and MHC in the isograft remained significantly lower at 64 and 53% of the respective rates measured simultaneously in the in situ working heart. Although total left ventricle RNA content in the isograft was unchanged by T4, alpha-MHC and SR Ca(2+)-ATPase mRNA concentrations were increased 181 and 208%, respectively, and the previously observed beta-MHC expression was completely prevented. These data indicate that, although T4 requires an increased hemodynamic load to stimulate cardiac protein synthesis, it is capable of directly altering the expression of at least two myocyte-specific genes. Therefore some of the phenotypic alterations observed with thyroid hormone treatment are the result of direct effects of the hormones on specific cardiac genes and independent of changes in cardiac growth.