Heart Vascular Function and Thyroid Hormone Receptors

心脏血管功能和甲状腺激素受体

• 批准号: 8140390
• 负责人: Wolfgang H Dillmann
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140390
• 关键词: Angiogenic Peptides; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Cardiac; Cardiac Myocytes; Cardiovascular system; Clinical; Consumption; Coronary; Coronary artery; Data; Endothelial Cells; Endothelium; Future; Genes; Healthcare; Heart; Heart Hypertrophy; Heart Rate; Hyperthyroidism; Infarction; Injury; Ischemia; Kidney; Knowledge; Lead; Link; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardium; Organ; Outcome; Oxygen Consumption; Perfusion; Peripheral; Peripheral Resistance; Physiological; Protein Isoforms; Receptor Signaling; Relaxation; Renal Blood Flow; Reperfusion Injury; Reperfusion Therapy; Research Proposals; Simulate; Skeletal Muscle; Stem cells; TNFRSF11B gene; Testing; Thyroid Hormone Receptor; Transgenic Mice; Translations; Tube; Vascular Endothelial Cell; Vascular resistance; Vasomotor; Veterans; angiogenesis; base; capillary; comparative; coronary perfusion; density; femoral artery; hemodynamics; improved; in vivo; loss of function; migration; mortality; myocardial infarct sizing; novel strategies; patient population; pre-clinical research; prevent; receptor expression; research study; success

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. PUBLIC HEALTH RELEVANCE: Decreased perfusion of the heart presents a significant medical problem. New approaches to increase cardiac perfusion and the density of blood vessels in heart muscle may significantly improve the outcome of myocardial infarcts. Increasing the expression of thyroid hormone receptors in endothelial cells may lead to an increase in coronary perfusion and have beneficial effects for ischemic heart disease.

描述（由申请人提供）： 缺血性心脏病仍然是一个重大的医学问题，除冠状动脉血运重建以外的其他方法没有长期成功以改善心肌灌注。甲状腺功能亢进会增加冠状动脉灌注并增强心脏毛细血管密度，但这些有益的血管作用伴随着不良的心脏变化，例如心率增加和心脏O2消耗。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）同工型TR1或TR2是否会在没有不良心脏或全身变化的情况下导致有益的血管作用。另外，TR同工型在EC中发挥作用的详细机制在很大程度上没有探索。我们生成了具有EC特异性表达或TR1和TR2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。在目的中，我们探索ECS中TR1或TR2表达的变化是否影响血管功能，尤其是冠状动脉灌注和冠状动脉收缩和松弛。此外，我们确定了介导这些变化的机制。初步结果表明，在没有不良影响的情况下，TR11在EC中的表达增加会导致冠状动脉灌注明显增加，例如心率增加，氧气消耗或全身性血管抗性的显着降低。在AIM II中，我们确定基于EC的TR1和TR2表达或缺失对心脏毛细管密度的影响。我们的初步数据表明，EC中TR2表达的变化发挥选择性效应明显增加了心脏毛细管密度，而TR1无效。在AIM III中，我们确定在EC中增加TR1或TR2表达以及恢复缺血再灌注（I/R）介导的TR水平降低是否会改善I/R介导的心脏损伤。初步结果表明，将心脏或EC暴露于I/R的状况大大降低了EC TR水平。此外，我们发现EC中的TR表达增加可以改善I/R介导的损伤，并在体内条件下降低梗塞大小。这些研究可能导致新的方法在没有不良影响的情况下通过增加心脏毛细管密度来改善冠状动脉灌注并增加底物交换。此外，将获得与EC中的TR动作相关的新知识。对退伍军人卫生保健的潜在影响：缺血性心脏病显着有助于退伍军人人群的发病率和死亡率。该提案的“临床前”研究表明，通过血管内皮细胞中甲状腺激素受体的表达，心脏微循环功能的显着改善，并降低了心肌梗死的大小。这些发现可能会导致未来方法的临床翻译。 公共卫生相关性： 心脏灌注的减少带来了一个重大的医学问题。增加心脏肌肉心脏灌注和血管密度的新方法可能会显着改善心肌梗死的结果。增加内皮细胞中甲状腺激素受体的表达可能会导致冠状动脉灌注的增加，并对缺血性心脏病具有有益的作用。