Heart Failure and Thyroid Hormone

描述（申请人提供）：心力衰竭（HF）是一个重要的临床问题，30%的HF患者血清T3水平明显降低。T3降低程度与HF相关死亡率之间存在密切的正相关。此外，心衰患者心肌核T3受体（TR）水平及TR应答基因表达降低。压力过载（PO）诱导的小鼠心肌肥厚（CH）和HF （CH/HF）也导致血清T3水平降低，心脏TR α和TR β水平显著降低，TR应答基因表达减少。目前尚不清楚CH/HF中T3和TR水平的降低以及由此导致的TR作用的减少是有益的、适应性的还是非适应性的反应。在Aim I中，我们将在体内功能研究中探索增加CH/HF心肌细胞（CM）中的TR作用是否会产生有益或有害的影响。我们将限制TR作用恢复到正常范围，避免甲状腺功能亢进。初步结果表明，增加chf /HF中TR α或TR β水平可显著改善钙通量和收缩功能。这些影响将在二元转基因小鼠中得到证实，允许在CM中基于四环素系统表达TR。我们的研究结果还表明，将TR水平恢复到正常范围是恢复收缩功能的关键组成部分，而不是T3替代。在Aim II中，我们将确定TR作用介导的心功能和生存变化的机制，并确定TR缺失对CH/HF心功能和生存的影响。初步研究结果表明，改变TR在CH/HF中的作用可通过TR β特异性机制显著影响脂肪酸氧化。此外，除了对细胞质钙通量的影响外，线粒体钙处理也得到了改善。此外，CH/HF中TR作用的增加显著减弱了NFAT3等不良自适应信号级联，也改变了Rafl-ERK的信号作用。将在小鼠中探索TR缺失的影响，允许CM中的TR α和TR β有条件地、定时地缺失。在Aim III中，我们探讨了chf /HF小鼠中TR作用的增加是否会导致心脏血管供应的增加，并确定了这些影响是如何介导的。初步数据显示，增强TR作用可导致CH/HF的毛细血管和小动脉密度显著增加。体外血管形成的初步结果表明，TR作用对内皮细胞产生直接影响，而不依赖于TR作用的血流动力学和代谢后果。这些研究将为甲状腺激素作用的变化对心力衰竭进展的贡献提供新的知识。

DESCRIPTION (provided by applicant): 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.