Cardiac hypertrophy and SERCa2 gene expression

心脏肥大和 SERCa2 基因表达

• 批准号: 7329163
• 负责人: Wolfgang H Dillmann
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329163
• 关键词: Adverse effects; Animals; Calcium; Calcium Channel; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cardiac; Cardiac Myocytes; Clinical; Complex; Congenital Heart Defects; Consumption; Cytoplasm; Dependovirus; Dilated Cardiomyopathy; Excision; FKBP1B gene; Failure; Functional disorder; Gene Expression; Generations; Heart; Heart Hypertrophy; Heart failure; L-Type Calcium Channels; Lead; Localized; Mediating; Medical; Mitochondria; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Outcome; Output; Performance; Production; Proteins; RyR2; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Staging; System; Systole; Tacrolimus Binding Proteins; Testing; Tetracycline; Tetracyclines; Time; Trans-Activators; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Viral Vector; Work; base; calcium indicator; calmodulin-dependent protein kinase II; human RIPK1 protein; improved; improved functioning; in vivo; inorganic phosphate; mortality; mouse model; pressure; release of sequestered calcium ion into cytoplasm; sarcoplasmic reticulum calcium ATPase; sorcin; transgene expression; uptake

DESCRIPTION (provided by applicant): Heart failure (HF) is an important clinical problem and abnormalities in cardiac myocyte (CM) calcium (Ca) handling make a significant contribution to contractile dysfunction. Increasing the activity of the Ca ATPase of the Sarcoplasmic reticulum (SERCa2) in hearts with pressure overload (PO) induced cardiac hypertrophy (CH) and decreased contractile function improves the Ca transient and leads to enhanced contractile performance. The long-term positive or negative consequences of conditional increases in SERCa2 activity at different stages of cardiac hypertrophy and heart failure (HF) are however unclear. In aim I, we will determine the long term positive or negative consequences of increasing SERCa2 activity in a conditional, inducible fashion to enhance the delayed diastolic Ca transient in hearts with PO induced HF. Our preliminary results indicate that increasing SERCa2 activity in PO mice with overt HF, may further curtail a limited energetic supply and impair work output. We will explore if increasing SERCa2 activity in a conditional, timed manner in hearts with different degrees of CH and HF can still improve the Ca transient and contractile function. Adeno associated virus based transgene delivery and transgenic animals allowing for tetracycline system or Cre LoxP based "stuffer" removal with conditional increases in SERCa2 activity are used. Abnormal Ca handling and contractile function in CH/HF hearts may be in part mediated by decreased sarcoplasmic reticulum (SR) Ca loading due to an increased diastolic Ca leak. In aim II, we will explore mechanisms to diminish the SR Ca leak using potentially ryanodine receptor interacting proteins like Sorcin, FKB12.6, and Homer1c. Our preliminary show significant positive effects of FKBP12.6,Sorcin on SR Ca loading. In aim III, we will pursue our preliminary findings that mitochondrial (Mito) Ca flux is abnormal in CM obtained from failing hearts and determine the underlying mechanisms. We will also pursue our preliminary results that Sorcin localizes to mitochondria and markedly improves abnormal Mito Ca handling. In addition, we will determine if HF induces changes in Mito Ca handling is correlated with diminished high-energy phosphate production and can be reverted towards normal.

描述（由申请人提供）：心力衰竭（HF）是一个重要的临床问题，心肌细胞（CM）钙（Ca）处理异常对收缩功能障碍有重要作用。在压力超负荷（PO）诱导的心肌肥厚（CH）和收缩功能降低的心脏中，增加肌浆网Ca ATP酶（SERCa 2）的活性改善了Ca瞬变并导致增强的收缩性能。然而，在心脏肥大和心力衰竭（HF）的不同阶段，SERCa 2活性条件性增加的长期积极或消极后果尚不清楚。在目的I中，我们将确定以条件性、诱导性方式增加SERCa 2活性以增强PO诱导的HF心脏中的延迟舒张Ca瞬变的长期积极或消极后果。我们的初步结果表明，增加SERCa 2活性PO小鼠明显HF，可能会进一步减少有限的能量供应和损害工作输出。我们将探讨在不同程度的CH和HF心脏中以条件性、定时方式增加SERCa 2活性是否仍能改善Ca瞬变和收缩功能。使用基于腺相关病毒的转基因递送和允许四环素系统或基于Cre LoxP的“填充物”去除以及SERCa 2活性的条件性增加的转基因动物。CH/HF心脏中的异常Ca处理和收缩功能可能部分由舒张期Ca泄漏增加引起的肌浆网（SR）Ca负荷降低介导。在目标II中，我们将探索使用潜在的兰尼碱受体相互作用蛋白如Sorcin，FKB 12.6和Homer 1c来减少SR Ca泄漏的机制。我们的初步研究表明FKBP 12.6、Sorcin对SR Ca负荷有显著的正效应。在目标III中，我们将继续我们的初步研究结果，即线粒体（Mito）钙流量是异常的CM从失败的心脏，并确定潜在的机制。我们还将继续我们的初步结果，Sorcin定位于线粒体，并显着改善异常Mito Ca处理。此外，我们将确定HF诱导的Mito Ca处理的变化是否与高能磷酸盐产生减少相关，并且可以恢复正常。

项目成果

Doxycycline inducible expression of SERCA2a improves calcium handling and reverts cardiac dysfunction in pressure overload-induced cardiac hypertrophy.

• DOI: 10.1152/ajpheart.00428.2004
• 发表时间: 2004-11
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Jorge A. Suarez;B. Gloss;D. Belke;Ying Hu;Brian T. Scott;T. Dieterle;Yun-Kyung Kim;M. Valencik;J. McDonald;W. Dillmann