CARDIAC HYPERTROPHY AND SERCA2 GENE EXPRESSION

心泵衰竭是一个主要的健康问题，而分子 导致心肌收缩能力下降的机制有 被积极调查的枪托目前基本上不为人知。在动物身上 与压力超负荷(PO)引起的心肌肥厚和人类 在大多数研究中，心脏疾病显著减少 肌浆网钙ATPase(SERCA2)的mRNA、蛋白水平和 酶的活性导致延迟的钙瞬变，这可能 有助于减缓舒张期的放松。功能贡献 SERCA2活性降低对心力衰竭的影响 已充分研究，目前尚不清楚SERCA2水平是否增加 心衰可改善心脏收缩功能。分子 内源性血管紧张素转换酶基因表达下降的机制 PO心脏中SERCA2基因的研究也不完全。我们 PO引起心肌细胞SERCA2酶水平升高的假说 心力衰竭会改善收缩功能，而心脏功能的改变 特异性核因子与通过特异性核因子传递信号的变化 途径将导致SERCA2基因表达下降。为了测试 在这一假设下，我们将追求三个目标。在第一个目标中，我们将 确定是否通过表达SERCA2转基因来提高SERCA2水平 在复制缺陷的人的转基因传递的中心 表达SERCA2转基因(Adv5SERCA2)的腺病毒载体 心脏导致SERCA2水平显著上升和改善 在接近正常范围的收缩行为。我们已经建造了 这种表达大量SERCA2的腺病毒载体 级别。病毒表达的SERCA2蛋白具有一定的功能 通过感染心肌细胞获得加速的钙 在感染了这种病毒的心肌细胞中的暂时性。兔心和宝心 大鼠将感染ADV5 SERCA2和SERCA2活性 将评估收缩功能。在第三个目标中，我们将 确定哪些特定的核转录因子和细胞 信号系统影响SERCA2基因转录并评估 有限数量的此类因素和信号系统的参与。 PO肥厚心脏SERCA2水平升高的测定 将改善心功能，使之接近正常范围，并增加 与分子机制相关的知识 这项研究将导致PO心脏的心功能下降 努力。

Cardiac pump failure presents a major health problem and the molecular mechanisms which contribute to decreased cardiac contractility are activately investigated butt are currently largely unknown. In animals with pressure overload (PO) induced cardiac hypertrophy and in human beings in a majority of studies, a marked decrease in cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) mRNA, protein levels and enzyme activity occur resulting in delayed calcium transients which may contribute to slowed diastolic relaxation. The functional contribution which the lowering of SERCA2 activity makes to heart failure has not been fully explored and it is currently unclear if increased SERCA2 levels in PO failing hearts would improve contractile function. The molecular mechanisms leading to the decrease in the expression of the endogenous SERCA2 gene in PO hearts have also only been incompletely explored. We hypothesize that increasing SERCA2 enzyme levels in myocytes from PO failing hearts will improve contractile function and that alteration in specific nuclear factors and changes in signaling through specific pathways will contribute to decreased SERCA2 gene expression. To test this hypothesis, we will pursue three aims. In the first aim, we will determine if increasing SERCA2 levels by expressing a SERCA2 transgene in the heart of transgenic delivery of a replication deficient human adenovirus 5 vectors expressing the SERCA2 transgene (Adv5 SERCA2) in PO hearts leads to a significant increase in SERCA2 levels and improvement in contractile behavior towards the normal range. We have constructed such an adenovirus vector which expresses significant amounts of SERCA2 levels. The virally expressed SERCA2 protein is functional as indicated by infection of cardiac myocytes and obtaining an accelerated calcium transient in myocytes infected with this virus. PO hearts of rabbits and rats will be infected with ADV5 SERCA2 and SERCA2 activity and contractile function will be evaluated. In the third aim, we will determine which specific nuclear transcription factors and cellular signaling systems influence SERCA2 gene transcription and evaluate the participation of a limited number of such factors and signaling systems. A determination if increasing SERCA2 levels in PO hypertrophied hearts will improve cardiac function toward the normal range, and additional knowledge related to the molecular mechanisms which contribute to decreased cardiac function in PO hearts will result from this research effort.