Thyroid hormone receptor expression in cardiovascular disease and pharmacology

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Sammanfattning: The heart is a major target organ for thyroid hormone actions. Thyroid hormone exerts effects on the myocardium, which are mediated by specific nuclear receptors. The thyroid hormone receptors (TR) are members of the steroid hormone receptor superfamily. These receptors regulate gene expression by binding to the promotor region of target genes as monomers, homodimers or heterodimers depending on the thyroid hormone response element (TRE) and the presence or absence of thyroid hormone. Aims of the study: 1. To evaluate the organ specific expression of TR rnRNA and protein distribution in different human tissues in relation to the levels in the heart. 2. To investigate if TR rnRNA expression is affected in heart failure that is due to dilated cardiomyopathy (DCM) or chronic valvular disease (CVD). 3. To investigate if TR subtype rnRNA expression is affected by amiodarone treatment. 4. To clarify whether AT-1 cardiomyocytes express TR rnRNA and protein. 5. To determine if propranolol may affect TR subtype rnRNA expression in mouse myocardium as well as in AT-1 cardiomyocytes. Conclusions: 1. Specific patterns of TR [alpha]1, [alpha]2, ß1, and ß2 mRNA and protein in heart and other tissues suggest tissue-specific expression of TR subtypes. The TR mRNA and protein concentration were rather high in heart compared to the other tissues. There is also a correlation between the pattern of TR rnRNA and protein distribution in heart. 2. TR 8, and ß2 mRNA show increased expression in the failing canine heart with DCM or CVD. 3. In mouse heart, amiodarone downregulated the levels of TR [alpha]1 and ß mRNA dosedependently in comparison to the control. There were however no differences in the TR[alpha]2 and TR62 rnRNA levels. 4. The AT-1 cardiomyocyte, like the mouse heart, expresses ligand-binding TR protein and TR [alpha]1 [alpha]2, ß1 and ß2 mRNA, although in lower quantities. This suggests a highly differentiated state of the AT-1 cardiomyocyte. This cell line can thus be suitable for studies of cellular effects of T3 on cardiac cells. 5. Propranolol downregulated the levels of TR[alpha]1 and ß1 rnRNA in mouse heart and of TRß1 rnRNA in AT-1 cardiomyocytes in comparison to control.

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