Abstract

Thyroid hormone exerts marked influences on the contractile and electrophysiological function of the heart. Preliminary studies indicate that mice with a thyroid hormone receptor alpha1 (TRalpha1) knockout have bradycardia, decreased speed of papillary muscle relaxation and decreased levels of the RNA encoding the transient outward potassium current KV4.2. In contrast, TR beta 1 knockout mice have normal heart rate and normal KV4.2 levels but decreased RNA for the delayed rectifier channel KV1.5.
The first aim will involve generating mice with a TRalpha knockout only in cardiac myocytes using the cre-lox system. Effects of the knockout on electrophysiological and contractile function will be determined. Gene expression of specific ion channel genes and other genes will also be determined. Cardiac effects of a novel T3 analog GC-1 will be explored. This analog has markedly decreased binding to TRalpha1 and a minimal effect on heart rate compared to T3.
In aim 2 similar contractile, electrophysiological and gene expression studies will be performed on TR beta knockout mice. In addition mice with a knockout of both TR's will be generated and studied.
In aim 3, the investigator will determine the mechanism of the specific TR isoform effects. Also the mechanisms of the effects of GC-1 will be studied.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025022-20
Application #
6182890
Study Section
Endocrinology Study Section (END)
Project Start
1979-05-01
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
20
Fiscal Year
2000
Total Cost
$239,494
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Hilal-Dandan, Randa; He, Huaping; Martin, Jody L et al. (2009) Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive Gi protein and cAMP. Am J Physiol Heart Circ Physiol 296:H728-34
Belke, Darrell D; Gloss, Bernd; Swanson, Eric A et al. (2007) Adeno-associated virus-mediated expression of thyroid hormone receptor isoforms-alpha1 and -beta1 improves contractile function in pressure overload-induced cardiac hypertrophy. Endocrinology 148:2870-7
Hu, Ying; Jones, S V Penelope; Dillmann, Wolfgang H (2005) Effects of hyperthyroidism on delayed rectifier K+ currents in left and right murine atria. Am J Physiol Heart Circ Physiol 289:H1448-55
Gloss, Bernd; Giannocco, Gisele; Swanson, Eric A et al. (2005) Different configurations of specific thyroid hormone response elements mediate opposite effects of thyroid hormone and GC-1 on gene expression. Endocrinology 146:4926-33
Swanson, Eric A; Gloss, Bernd; Belke, Darrell D et al. (2003) Cardiac expression and function of thyroid hormone receptor beta and its PV mutant. Endocrinology 144:4820-5
Dillmann, W H (2002) Cellular action of thyroid hormone on the heart. Thyroid 12:447-52
Gloss, B; Trost, S; Bluhm, W et al. (2001) Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology 142:544-50
Trost, S U; Swanson, E; Gloss, B et al. (2000) The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141:3057-64
Gloss, B; Villegas, S; Villarreal, F J et al. (2000) Thyroid hormone-induced stimulation of the sarcoplasmic reticulum Ca(2+) ATPase gene is inhibited by LIF and IL-6. Am J Physiol Endocrinol Metab 278:E738-43
Villegas, S; Villarreal, F J; Dillmann, W H (2000) Leukemia Inhibitory Factor and Interleukin-6 downregulate sarcoplasmic reticulum Ca2+ ATPase (SERCA2) in cardiac myocytes. Basic Res Cardiol 95:47-54

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