Heart failure (HF) is an important clinical problem and 30% of HF patients have a marked lowering of serum T3 levels. A close positive correlation exists between the extent of T3 lowering and HF related mortality. In addition, cardiac nuclear T3 receptor (TR) levels and the expression of TR responsive genes are decreased in HF patients. Pressure overload (PO) induced cardiac hypertrophy (CH) and HF (CH/HF) in mice also leads to decreased serum T3 levels and a marked decrease in cardiac TR alphal and TR betal levels with diminished TR responsive gene expression. It is currently unclear if the lowered T3 and TR levels and the resulting decrease in TR action in CH/HF presents a beneficial, adaptive or mal-adaptive response.
In Aim I we will explore, in in vivo function studies, if increasing TR action in cardiac myocytes (CM) of CH/HF results in beneficial or detrimental effects. We will limit the restitution of TR action to the normal range avoiding a hyperthyroid state. Preliminary results show that increasing TR alphal or TR betal levels in CH/HF markedly improves calcium (Ca) flux and contractile function. These effects will be confirmed in binary transgenic mice allowing for tetracycline system based expression of TR in CM. Our findings also indicate that restoring TR levels back to the normal range is the crucial component to rescue contractile function instead of T3 substitution.
In Aim II we will identify mechanisms which underlie TR action mediated changes in cardiac function and survival and determine the influence of TR deletion on cardiac function and survival in CH/HF. Preliminary findings indicate that altering TR action in CH/HF markedly influences fatty acid oxidation, exerted through a TR beta specific mechanism. In addition, mitochondrial Ca handling is improved in addition to influences on cytosolic Ca flux. Furthermore increasing TR action in CH/HF markedly attenuates mal-adaptive signaling cascade, like NFAT3 signaling and also alters signaling action of Rafl-ERK. Effects of TR deletion will be explored in mice allowing for conditional, timed deletion of TR alpha and TR beta in CM.
In Aim III we explore if increasing TR action in mice with CH/HF results in increased cardiac vascular supply and determine how these effects are mediated. Preliminary data show that enhancing TR action leads to a marked increase in capillary and arteriolar density in CH/HF. Preliminary results using ex vivo vascular tube formation indicate that TR action exerts direct effects on endothelial cells, independent of the hemodynamic and metabolic consequences of TR action. These studies will provide new knowledge related to the contribution which changes in thyroid hormone action make to the progression of heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-P (02))
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Liang, Isabella Y
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Makino, Ayako; Wang, Hong; Scott, Brian T et al. (2012) Thyroid hormone receptor-? and vascular function. Am J Physiol Cell Physiol 302:C1346-52
Suarez, Jorge; Scott, Brian T; Suarez-Ramirez, Jorge A et al. (2010) Thyroid hormone inhibits ERK phosphorylation in pressure overload-induced hypertrophied mouse hearts through a receptor-mediated mechanism. Am J Physiol Cell Physiol 299:C1524-9
Makino, Ayako; Suarez, Jorge; Wang, Hong et al. (2009) Thyroid hormone receptor-beta is associated with coronary angiogenesis during pathological cardiac hypertrophy. Endocrinology 150:2008-15