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外，其他方法在改善心肌灌注方面没有长期成功。甲亢增加冠脉血流，增加心脏毛细血管密度，但这些有益的血管效应伴随着不良的心脏变化，如心率增加和心脏耗氧量增加。目前尚不清楚仅在血管内皮细胞(ECs)中增加甲状腺激素受体(TR1)或TR2亚型的表达是否能在没有不良心脏或全身变化的情况下产生有益的血管效应。此外，TRR亚型在内皮细胞中发挥作用的详细机制在很大程度上尚不清楚。我们产生了EC特异性表达或缺失TR1和TR2的小鼠，以探索对血管功能的影响，重点是冠脉灌注量和心脏毛细血管密度。在目的I中，我们探讨内皮细胞TR1或TR2表达的变化是否影响血管功能，特别是冠脉血流灌注和冠脉收缩和松弛。此外，我们还确定了调解这些变化的机制。初步结果显示，TR11在内皮细胞中的表达增加，在没有心率、耗氧量或全身血管阻力显著降低等不良影响的情况下，会显著增加冠脉灌注量。在AIM II中，我们确定了基于EC的TR1和TR2的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，内皮细胞TR2表达的变化具有选择性，明显增加心脏毛细血管密度，而不受TR1的影响。在目的III中，我们确定增加内皮细胞TR1或TR2的表达和恢复缺血再灌注(I/R)介导的TRR水平的降低是否改善了I/R介导的心脏损伤。初步结果显示，心脏或内皮细胞暴露在类似I/R的条件下可显著降低EC受体水平。此外，我们还发现，在活体条件下，增加内皮细胞中TRR的表达可以减轻I/R介导的损伤并缩小梗塞面积。这些研究可能导致在没有不良影响的情况下通过增加心脏毛细血管密度来改善冠状动脉血流灌注和增加底物交换的新方法。此外，还将获得与欧洲共同体技术援助行动有关的新知识。对退伍军人医疗保健的潜在影响：在退伍军人患者群体中，缺血性心脏病极大地增加了发病率和死亡率。这项建议的“临床前”研究表明，通过血管内皮细胞甲状腺激素受体的表达，心脏微循环功能得到显著改善，心肌梗死面积减少。这些发现可能会在未来的方法中导致临床翻译。

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.