Heart Vascular Function and Thyroid Hormone Receptors

描述（由申请人提供）： 缺血性心脏病仍然是一个重要的医学问题，除了冠状动脉血运重建之外，其他方法在改善心肌灌注方面没有长期的成功。甲状腺功能亢进症增加冠状动脉灌注并增强心脏毛细血管密度，但这些有益的血管效应伴随着不良的心脏变化，如心率和心脏O2消耗增加。目前尚不清楚仅在血管内皮细胞（EC）中增加甲状腺激素受体（TR）亚型TR 1或TR 2的表达是否可以在不存在不良心脏或全身变化的情况下产生有益的血管效应。此外，TR亚型在EC中发挥作用的详细机制在很大程度上尚未探索。我们产生了EC特异性表达或TR 1和TR 2缺失的小鼠，以探索对血管功能的影响，重点是冠状动脉灌注和心脏毛细血管密度。在目的I中，我们探讨EC中TR 1或TR 2表达的变化是否影响血管功能，特别是冠状动脉灌注和冠状动脉收缩和舒张。此外，我们还确定了介导这些变化的机制。初步结果表明，在没有不良影响（如心率增加、耗氧量增加或全身血管阻力显著降低）的情况下，EC中TR 11表达增加导致冠状动脉灌注显著增加。在目的II中，我们确定了基于EC的TR 1和TR 2表达或缺失对心脏毛细血管密度的影响。我们的初步数据表明，TR 2在EC表达的变化发挥选择性作用，显着增加心脏毛细血管密度与TR 1没有影响。在目的III中，我们确定增加EC中TR 1或TR 2表达和恢复缺血再灌注（I/R）介导的TR水平降低是否改善I/R介导的心脏损伤。初步结果显示，将心脏或EC暴露于I/R样条件显著降低EC TR水平。此外，我们发现在体内条件下增加EC中TR表达可改善I/R介导的损伤并减小梗死面积。这些研究可能会导致新的方法，以改善冠状动脉灌注和增加底物交换，增加心脏毛细血管密度的情况下，不良反应。此外，还将获得与EC中TR作用相关的新知识。对退伍军人医疗保健的潜在影响：缺血性心脏病显著增加了退伍军人患者人群的发病率和死亡率。该提案的“临床前”研究表明，通过在血管内皮细胞中表达甲状腺激素受体，心脏微循环功能得到显著改善，心肌梗死面积减少。这些发现可能会导致临床翻译在未来的方法。

DESCRIPTION (provided by applicant): Ischemic heart disease continues to be a significant medical problem and approaches other than coronary artery revascularization have had no long term success to improve myocardial perfusion. Hyperthyroidism increases coronary perfusion and enhances cardiac capillary density but these beneficial vascular effects are accompanied by undesirable cardiac changes like increases in heart rate and cardiac O2 consumption. It is currently unclear if increasing the expression of thyroid hormone receptor (TR) isoforms TR1 or TR2 only in vascular endothelial cells (ECs) can result in beneficial vascular effects in the absence of undesirable cardiac or systemic changes. In addition the detailed mechanisms by which TR isoforms exert their effects in ECs are largely unexplored. We generated mice with EC specific expression or deletion of TR1 and TR2 to explore effects on vascular function with a focus on coronary perfusion and cardiac capillary density. In Aim I we explore if changes in TR1 or TR2 expression in ECs effects vascular function especially coronary perfusion and coronary artery contraction and relaxation. In addition we identify mechanisms which mediate these changes. Preliminary results show that increased expression of TR11 in ECs leads to a marked increase in coronary perfusion in the absence of undesirable effects like increases in heart rate, oxygen consumption, or a significant decrease in systemic vascular resistance. In Aim II we determine the effects of EC-based TR1 and TR2 expression or deletion on cardiac capillary density. Our preliminary data show that changes of TR2 expression in ECs exerts selective effects markedly increasing cardiac capillary density with no effect by TR1. In Aim III we determine if increasing TR1 or TR2 expression in ECs and restoring ischemia reperfusion (I/R) mediated decreases in TR levels ameliorates I/R mediated cardiac injury. Preliminary results show that exposing hearts or ECs to I/R like conditions significantly lowers EC TR levels. In addition we find that increasing TR expression in ECs ameliorates I/R mediated injury and decreases infarct size under in vivo conditions. The studies may lead to novel approaches to improve coronary perfusion and increase substrate exchange by increasing cardiac capillary density in the absence of undesirable effects. In addition new knowledge related to TR action in ECs will be obtained. POTENTIAL IMPACT ON VETERANS HEALTH CARE: Ischemic heart disease significantly contributes to morbidity and mortality in the veteran patient population. The "preclinical" research of this proposal demonstrates significant improvement in cardiac microcirculatory function and decreased myocardial infarct size by expression of thyroid hormone receptors in vascular endothelial cells. These findings may lead to clinical translation in future approaches.