THYROIDAL REGULATION OF CARDIAC SODIUM/POTASSIUM ATPASE EXPRESSION AND ENERGETICS

心脏钠/钾ATP酶表达和能量的甲状腺调节

• 批准号: 6564805
• 负责人: FARAMARZ ISMAIL-BEIGI
• 金额: $ 17.41万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564805
• 关键词: bioenergetics; cardiac myocytes; enzyme activity; gene expression; genetic mapping; genetic transcription; genetic translation; heart contraction; heart metabolism; hormone regulation /control mechanism; laboratory rat; messenger RNA; myocardium; posttranscriptional RNA processing; sodium potassium exchanging ATPase; thyroid hormones

Na+, K+-activated adenosine triphosphatase (Na, K-ATPase) is a ubiquitous energy transducing integral plasma membrane protein whose activity is of critical importance to the normal function of virtually all animal cells. In the heart the enzyme represents the cellular receptor for digitalis glycosides and its abundance and activity is significantly stimulated by the action of thyroid hormone (T3). The stimulatory effect of T3 on energy metabolism of the heart in vivo is a consequence of the direct actions of the hormone on cardiac myocytes as well as the increase in cardiac contractile work (cardiac output. in response to enhanced energy demand by other tissues. It has also been noted that the heart in hyperthyroid humans and animals manifests a reduction in functional "reserve" and maximal work capacity that is associated with a marked reduction in myocardial creatine-phosphocreatine pool. Such hearts are hence prone to fail if stimulated to work at or near maximal levels. The objectives of the proposed research program are two-fold. 1) To define the cellular and molecular mechanisms by which the abundance and activity of Na, K-ATPase is regulated in the myocardium, and 2) To define the role of thyroid hormone on myocardial creatine transport and metabolism, and to delineate the energetic mechanism underlying the decrease in functional "reserve" and maximal work capacity of the hyperthyroid heart. The proposed studies are focused on three Specific Aims: AIM I. Determine sequences contained in the 3'-untranslated region of alpha1-, alpha2-, and beta1-mRNA transcripts (cis-elements) and trans- acting factors that control the turnover of the mRNAs in the myocardium under basal and T3- stimulated conditions. AIM II. Characterize cis-elements and trans-acting factors that control the translational efficiency of the different beta1- mRNA species expressed in the heart, and determine whether T3 has an effect on the control of translation. AIM III. Determine the mechanism by which thyroid hormone controls the content of creatine-phosphocreatine pool in the heart, and define the role of altered creatine metabolism on the contractile function of the heart. Results of studies proposed in this project will increase our understanding of mechanisms mediating thyroidal regulation of myocardial Na, K-ATPase expression and cardiac bioenergetics. The studies are highly relevant to the pathogenesis of a variety of human diseases and conditions including congestive heart failure, salt and water imbalance, alterations in metabolism, and obesity.

Na+，K+激活的腺苷三磷酸酶（Na，K-ATP酶）是一种普遍存在的能量转导膜蛋白，其活性对几乎所有动物细胞的正常功能都至关重要。在心脏中，该酶代表洋地黄苷的细胞受体，其丰度和活性受到甲状腺激素（T3）作用的显着刺激。T3对体内心脏能量代谢的刺激作用是激素对心肌细胞的直接作用以及心脏收缩功（心输出量）增加的结果。以响应其它组织的增强的能量需求。还注意到，甲状腺功能亢进的人类和动物的心脏表现出功能性“储备”和最大工作能力的降低，这与心肌肌酸-磷酸肌酸池的显著降低有关。因此，如果在最大水平或接近最大水平的刺激下工作，这样的心脏容易衰竭。拟议的研究计划的目标是双重的。1)明确心肌Na，K-ATP酶丰度和活性调节的细胞和分子机制; 2）明确甲状腺激素对心肌肌酸转运和代谢的作用，阐明甲亢心脏功能储备和最大作功能力下降的能量机制。拟议的研究集中在三个具体目标：AIM I。 确定α 1、α 2和β 1-mRNA转录物（顺式元件）3 '非翻译区中所含的序列以及在基础和T3刺激条件下控制心肌中mRNA周转的反式作用因子。AIM II.表征控制心脏中表达的不同β 1- mRNA种类的翻译效率的顺式元件和反式作用因子，并确定T3是否对翻译控制有影响。AIM III. 确定甲状腺激素控制心脏中肌酸-磷酸肌酸池含量的机制，并定义肌酸代谢改变对心脏收缩功能的作用。本项目的研究结果将增加我们对甲状腺调节心肌Na，K-ATP酶表达和心脏生物能量学机制的理解。这些研究与多种人类疾病和病症的发病机制高度相关，包括充血性心力衰竭、盐和水失衡、代谢改变和肥胖。