THYROIDAL REGULATION OF CARDIAC SODIUM/POTASSIUM ATPASE EXPRESSION AND ENERGETICS

Na+，K+激活的三磷酸腺苷酶(Na，K-ATPase)是一种普遍存在的能量传递完整的质膜蛋白，其活性对几乎所有动物细胞的正常功能至关重要。在心脏，该酶代表洋地黄糖苷的细胞受体，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。以响应其他组织增加的能量需求。人们还注意到，甲亢人和动物的心脏表现出功能“储备”和最大工作能力的减少，这与心肌肌酸-磷酸肌酸池显著减少有关。因此，如果这种心脏受到刺激，工作在或接近最大水平，就容易衰竭。拟议的研究计划的目标有两个。1)明确心肌Na，K-ATPase丰度和活性调节的细胞和分子机制；2)明确甲状腺激素在心肌肌酸转运和代谢中的作用，阐明甲亢心脏功能“储备”和最大作功能力下降的能量机制。这些研究主要集中在三个特定的目标上：目的一、确定α1、α2和β1基因转录产物的3‘非翻译区(顺式元件)中包含的序列以及控制基础和T3刺激条件下心肌中mRNAs翻转的反式作用因子。目的II.鉴定控制心脏表达的不同β1-mRNA物种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。目的III.确定甲状腺激素控制心脏肌酸-磷酸肌酸库含量的机制，明确肌酸代谢改变对心脏收缩功能的影响。本项目的研究结果将加深我们对甲状腺调节心肌Na，K-ATPase表达和心脏生物能量学机制的理解。这些研究与各种人类疾病和状况的发病机制高度相关，包括充血性心力衰竭、盐和水失衡、新陈代谢改变和肥胖。

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.