Cardiac hypertrophy and SERCa2 gene expression

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）处理异常是导致收缩功能障碍的重要原因。在压力过载（PO）引起心脏肥厚（CH）和收缩功能下降的心脏中，增加肌浆网（SERCa2） Ca atp酶的活性可以改善Ca瞬态并导致收缩性能增强。然而，在心脏肥厚和心力衰竭（HF）的不同阶段，SERCa2活性条件性增加的长期积极或消极后果尚不清楚。在目的1中，我们将以有条件的、诱导的方式确定SERCa2活性增加的长期积极或消极后果，以增强PO诱导HF心脏的延迟舒张期钙瞬态。我们的初步结果表明，在明显HF的PO小鼠中，SERCa2活性的增加可能进一步减少有限的能量供应并损害工作输出。我们将探索在不同程度CH和HF的心脏中，有条件地、定时地增加SERCa2活性是否仍然可以改善Ca的瞬态和收缩功能。基于腺相关病毒的转基因传递和转基因动物允许四环素系统或基于Cre LoxP的“填充物”去除，SERCa2活性有条件地增加。CH/HF心脏的异常钙处理和收缩功能可能部分是由于舒张期钙泄漏增加导致肌浆网（SR）钙负荷减少所致。在aim II中，我们将探索利用Sorcin、FKB12.6和Homer1c等潜在的ryanodine受体相互作用蛋白减少SR - Ca泄漏的机制。我们初步发现FKBP12.6，Sorcin对SR Ca的加载有显著的正向影响。在aim III中，我们将继续我们的初步发现，即从衰竭心脏获得的CM中线粒体（Mito） Ca通量异常，并确定潜在的机制。我们还将继续我们的初步结果，即Sorcin定位于线粒体并显着改善异常的水户钙处理。此外，我们将确定HF诱导的水户钙处理变化是否与高能磷酸盐产量减少相关，是否可以恢复正常。

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.