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患者的血清T3水平显著降低。T3降低的程度与心力衰竭相关死亡率密切相关。此外，心衰患者心肌核T_3受体水平及受体反应基因表达均降低。压力超负荷(PO)引起的小鼠心肌肥厚(CH)和心衰(CH/HF)也导致血清T_3水平下降，心脏T_3和T_Rβ水平显著降低，T_R反应基因表达减弱。目前尚不清楚在CH/HF中，T3和TR值的降低以及由此导致的TR值的降低是一种有益的、适应性的还是不良的适应性反应。在目标I中，我们将在体内功能研究中探索CH/HF在心肌细胞(CM)中增加受体作用是否会产生有益或有害的影响。我们将把TR活动的恢复限制在正常范围内，避免出现甲亢状态。初步结果表明，在CH/HF中，增加TrAlphal或TrBetal水平可显著改善钙(Ca)流量和收缩功能。这些效应将在允许基于四环素系统的四环素系统在CM中表达的二元转基因小鼠中得到证实。我们的发现还表明，将TR值恢复到正常范围是挽救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Trp作用介导的心功能和存活率变化的机制，并确定Trr缺失对心功能和CHF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，这种影响是通过trβ特异性机制实现的。此外，除了对细胞内钙通量的影响外，线粒体对钙的处理也得到了改善。此外，在CH/HF中增加tr的作用可显著减弱NFAT3信号等不良适应性信号级联反应，并改变rafl-ERK的信号作用。将在小鼠身上探索tr缺失的影响，允许有条件地、定时地删除CM中的trα和trβ。在Aim III中，我们探索在CH/HF小鼠中增加tr作用是否会导致心脏血管供应增加，并确定这些影响是如何介导的。初步数据显示，增强tr作用可使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，与tr作用的血流动力学和代谢后果无关。这些研究将提供有关甲状腺激素活动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.