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)处理的异常是导致收缩功能障碍的重要原因。在压力超负荷(PO)致心肌肥厚(CH)和收缩功能下降的心脏中，提高肌浆网钙ATPase(SERCA2)的活性可改善钙瞬变，导致收缩性能增强。然而，在心肌肥厚和心力衰竭(HF)的不同阶段，SERCA2活性有条件增加的长期积极或消极后果尚不清楚。在目标I中，我们将确定以一种有条件的、可诱导的方式增加SERCA2活性以增强PO诱导的心衰心脏舒张期延迟钙瞬变的长期积极或消极后果。我们的初步结果表明，在PO小鼠中增加SERCA2活性，可能会进一步减少有限的能量供应，损害做功输出。我们将探讨在不同程度的充血性心力衰竭和心力衰竭的心脏中，以有条件的、定时的方式增加SERCA2活性是否仍然可以改善钙瞬变和收缩功能。使用了基于腺相关病毒的转基因传递和允许四环素系统或基于Cre loxP的“填充物”去除并有条件地增加SERCA2活性的转基因动物。CH/HF心脏的钙处理和收缩功能异常可能部分是由于舒张期钙渗漏增加而导致肌浆网钙负荷降低所致。在AIM II中，我们将探索使用潜在的兰诺定受体相互作用蛋白，如Sorcin，FKB12.6和Hmer 1c来减少SR Ca泄漏的机制。我们的初步研究显示FKBP12.6、Sorin对肌浆网钙负荷有显著的正向作用。在目标III中，我们将继续我们的初步发现，从衰竭的心脏获得的心肌线粒体(MITO)钙通量异常，并确定其潜在的机制。我们还将追求我们的初步结果，即索尔辛定位于线粒体，并显著改善异常的有丝分裂钙处理。此外，我们将确定HF是否会导致Mito Ca处理的变化与高能磷酸盐产量的减少相关，并可以恢复到正常水平。

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.