Heart Failure and Thyroid Hormone

描述（由申请人提供）：心力衰竭（HF）是一个重要的临床问题，30%的HF患者血清T3水平显著降低。T3降低的程度与HF相关死亡率之间存在密切的正相关。此外，HF患者心脏核T3受体（TR）水平和TR应答基因的表达降低。压力超负荷（PO）诱导的小鼠心脏肥大（CH）和HF（CH/HF）也导致血清T3水平降低和心脏TR β 1和TR β 1水平显著降低，同时TR应答基因表达减少。目前尚不清楚CH/HF中降低的T3和TR水平以及由此导致的TR作用的降低是否呈现有益的、适应性的或适应不良的反应。在目的I中，我们将探索，在体内功能研究中，如果增加TR的CH/HF的心肌细胞（CM）的作用结果是有益的还是有害的。我们将限制恢复TR行动的正常范围，避免甲状腺功能亢进的状态。初步结果表明，增加CH/HF中的TR β 1或TR β 1水平显著改善钙（Ca）通量和收缩功能。这些效应将在允许基于四环素系统的TR在CM中表达的二元转基因小鼠中得到证实。我们的研究结果还表明，恢复TR水平回到正常范围是拯救收缩功能的关键组成部分，而不是T3替代。在目的II中，我们将确定TR作用介导的心脏功能和存活率变化的机制，并确定TR缺失对CH/HF患者心脏功能和存活率的影响。 初步研究结果表明，改变CH/HF中的TR作用显著影响脂肪酸氧化，通过TR β特异性机制发挥作用。此外，线粒体Ca处理除了对细胞溶质Ca通量的影响之外还得到改善。此外，增加CH/HF中的TR作用显著地减弱了不良适应性信号传导级联，如NFAT 3信号传导，并且还改变了Rafl-ERK的信号传导作用。将在允许CM中TR α和TR β的条件性定时缺失的小鼠中探索TR缺失的影响。在目的III中，我们探讨了CH/HF小鼠中增加TR作用是否会导致心脏血管供应增加，并确定这些作用是如何介导的。初步数据显示，增强TR作用导致CH/HF中毛细血管和小动脉密度显著增加。使用离体血管管形成的初步结果表明，TR作用对内皮细胞产生直接影响，独立于TR作用的血液动力学和代谢后果。这些研究将提供有关甲状腺激素作用变化对心力衰竭进展的贡献的新知识。

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.