Heart Failure and Thyroid Hormone

心力衰竭和甲状腺激素

• 批准号: 7899936
• 负责人: Wolfgang H Dillmann
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899936
• 关键词: Abbreviations; Animal Model; Antibodies; Attenuated; Back; Blood Vessels; Blood capillaries; Body Weight; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Clinical; Consumption; Coronary; Cytomegalovirus; Data; Dependovirus; Deterioration; Dose; Doxycycline; Endothelial Cells; Enhancers; Gene Expression; Genes; Green Fluorescent Proteins; Heart; Heart Hypertrophy; Heart Rate; Heart failure; Hypertrophy; Iodide Peroxidase; Knock-out; Knockout Mice; Knowledge; Left ventricular structure; Long-Term Effects; Mediating; Medical; Metabolic; Mitochondria; Morbidity - disease rate; Mus; Myosin Heavy Chains; Nonesterified Fatty Acids; Normal Range; Nuclear; Oxygen; Patients; Physiological; Protein Isoforms; RNase protection assay; Rattus; Research Personnel; Response Elements; Sarcoplasmic Reticulum; Serum; Signal Transduction; Steroid Receptors; Syndrome; System; T cell activating factor; Tamoxifen; Testing; Tetracyclines; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Triiodothyronine; Triiodothyronine Receptors; Tube; Vascular Endothelial Cell; Vascular System; Vascular blood supply; Ventricular; Weight; angiogenesis; base; capillary; constriction; density; fatty acid oxidation; gain of function; hemodynamics; hormone response element; improved; in vivo; loss of function; mitochondrial uncoupling protein 3; mortality; mouse model; myosin light chain 2; oxidation; phospholamban; pressure; programs; promoter; receptor expression; release of sequestered calcium ion into cytoplasm; response

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.

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水平明显降低。在T3降低与HF相关死亡率之间存在密切的正相关。此外，HF患者的心脏核T3受体（TR）水平和TR反应基因的表达降低。小鼠的压力超负荷（PO）诱导的心脏肥大（CH）和HF（CH/HF）也导致血清T3水平降低，心脏TRα和TR稳定水平显着降低，而TR响应基因表达降低。目前尚不清楚CH/HF中TR作用的降低是否降低，而导致的TR作用降低会提出有益的，适应性的或MAL自适应的反应。在AIM我将在体内功能研究中探索，如果CH/HF的心肌细胞（CM）增加TR作用会导致有益或有害效应。我们将将TR作用的恢复原状限制在避免甲状腺功能亢进状态的正常范围内。初步结果表明，CH/HF中的Tr alphal或Tr稳定水平升高显着改善钙（CA）通量和收缩功能。这些作用将在二元转基因小鼠中得到确认，从而允许基于四环素系统的TR在CM中的表达。我们的发现还表明，将TR水平恢复到正常范围是挽救收缩功能而不是T3替代的关键组成部分。在AIM II中，我们将确定TR动作介导的心脏功能变化和生存的机制，并确定TR缺失对CH/HF中心脏功能和生存的影响。 初步发现表明，CH/HF中的TR作用改变明显影响脂肪酸氧化，该脂肪酸氧化是通过TRβ的特定机制施加的。此外，除了对胞质CA通量的影响外，线粒体CA的处理还得到了改善。此外，在CH/HF中增加TR作用明显减弱了诸如NFAT3信号传导以及改变RAFL-ERK的信号动作之类的MAL自适应信号传导级联。将在小鼠中探索TR缺失的效果，从而允许在CM中进行有条件的，定时缺失和TRβ。在AIM III中，我们探讨了CH/HF小鼠的TR作用是否增加会导致心脏血管供应增加，并确定这些作用是如何介导的。初步数据表明，增强TR动作会导致CH/HF中的毛细血管和小动脉密度显着增加。使用离体血管形成的初步结果表明，TR作用对内皮细胞发挥直接影响，与TR作用的血流动力学和代谢后果无关。这些研究将提供与甲状腺激素作用变化对心力衰竭发展的贡献有关的新知识。