Regulation of sarcoplasmic reticulum calcium release in heart failure

心力衰竭中肌浆网钙释放的调节

• 批准号: 8064236
• 负责人: Xander H.T. Wehrens
• 金额: $ 6.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064236
• 关键词: Affinity Chromatography; Animal Model; Biochemical; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cardiac; Cardiac Myocytes; Cause of Death; Chronic; Congestive Heart Failure; Coronary artery; Data; Defect; Depressed mood; Development; Echocardiography; Enzymes; Frequencies; Functional disorder; Genetic; Goals; Hand; Heart; Heart Hypertrophy; Heart Rate; Heart failure; Image; Ion Exchange; Ligation; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measurement; Measures; Mediating; Modeling; Molecular; Mus; Muscle Cells; Myocardial; Peptides; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphorylation Site; Phosphotransferases; Proteins; Regulation; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Serine; Serine Phosphorylation Site; Signal Transduction; Staging; Testing; Therapeutic; Time; Transgenic Mice; United States; Ventricular; calmodulin-dependent protein kinase II; hemodynamics; in vivo; mouse model; multidisciplinary; prevent; protective effect; public health relevance; research study; voltage

DESCRIPTION (provided by applicant): Ryanodine receptors (RyR2) regulate intracellular Ca2+ release from the sarcoplasmic reticulum (SR), and are important determinants of cardiac contractility. We have recently demonstrated that the enzyme Ca2+/calmodulin-dependent protein kinase (CaMKII) phosphorylates serine 2814 (S2814) on RyR2, which increases SR Ca2+ release and serves as an important regulatory mechanism to enhance cardiac contractility at faster heart rates. On the other hand, upregulated CaMKII activity has been identified as an important signaling defect in congestive heart failure (CHF). Chronic CaMKII phosphorylation of RyR2 has been proposed as a principal cause of enhanced SR Ca2+ leak, which is an important determinant of contractile dysfunction in CHF. The long-term goal of this project is to define the cellular/molecular mechanisms by which CaMKII regulates RyR2-mediated SR Ca2+ release and cardiac contractility in normal and failing hearts, by studying knockin mice in which the CaMKII phosphorylation site serine 2814 (S2814) on RyR2 is either inactivated (S2814A) or constitutively activated (S2814D). Our hypothesis is that in normal hearts, CaMKII phosphorylates S2814 on RyR2 to increase SR Ca2+ release and cardiac contractility, whereas in failing hearts chronic CaMKII phosphorylation of RyR2-S2814 enhances diastolic leak of Ca2+ from the SR, which interferes with SR Ca2+ loading and causes depressed contractility. The specific aims are to: 1) Define the effects of CaMKII phosphorylation of RyR2 on cardiac contractility; 2) Determine whether chronic CaMKII phosphorylation of RyR2-S2814 is sufficient to induce heart failure; 3) Evaluate whether inhibition of CaMKII phosphorylation of RyR2 is therapeutic in heart failure. We propose to conduct multidisciplinary studies ranging from in vivo studies in genetically-altered mice, Ca2+ imaging studies in isolated cardiomyocytes, and biochemical and single channel measurements of RyR2 Ca2+ release channels. It is anticipated that these studies will advance our understanding of CaMKII-dependent mechanisms underlying the regulation of cardiac contractility in both normal and failing hearts. The animal models developed for this project may be particularly useful for the development of new drugs for the treatment of congestive heart failure, the leading cause of death in the United States. PUBLIC HEALTH RELEVANCE: Leaky intracellular calcium release channels are an important determinant of contractile dysfunction in heart failure. We will use genetic mouse models to study how the enzyme calmodulin-dependent kinase regulates the activity of intracellular calcium release channels in healthy and failing hearts. These studies may facilitate the development of new pharmacological approaches for the treatment of heart failure, the leading cause of death in the United States.

描述（由申请人提供）：ryanodine受体（RYR2）调节细胞内Ca2+从肌质网（SR）释放，并且是心脏收缩性的重要决定因素。我们最近证明，酶Ca2+/钙调蛋白依赖性蛋白激酶（CAMKII）在RYR2上磷酸化丝氨酸2814（S2814），从而增加了SR Ca2+释放，并作为一种重要的调节机制，可增强以富裕的心脏速率增强心脏收缩性。另一方面，上调的CAMKII活性已被确定为充血性心力衰竭（CHF）的重要信号缺陷。已提出了RYR2的慢性CAMKII磷酸化，这是SR CA2+泄漏增强的主要原因，这是CHF收缩功能障碍的重要决定因素。该项目的长期目标是定义CAMKII调节RYR2介导的SR Ca2+释放和心脏不衰弱的camkii磷酸化甲磷酸化位点2814（s2814）在正常和失败心脏中调节RYR2介导的SR CA2+释放和心脏收缩力的细胞/分子机制。 （S2814D）。我们的假设是，在正常的心脏中，CaMKII磷酸化RYR2上的S2814增加了SR Ca2+释放和心脏收缩性，而在失败的心脏中，RYR2-S2814的慢性CAMKII磷酸化增强了SR的Ca2+ SR渗漏的舒张期Ca2+ SR的渗透，从而干扰了SR CA2+加载损失的损失。具体目的是：1）定义RYR2 CAMKII磷酸化对心脏收缩性的影响； 2）确定RYR2-S2814的慢性CAMKII磷酸化是否足以诱导心力衰竭； 3）评估RYR2的CAMKII磷酸化抑制是否在心力衰竭中是治疗性的。我们建议进行多学科研究，包括在遗传变化小鼠的体内研究，分离的心肌细胞中的Ca2+成像研究以及RYR2 CA2+释放通道的生化和单个通道测量。可以预料，这些研究将提高我们对正常和失败心脏中心脏收缩性调节的CAMKII依赖机制的理解。为该项目开发的动物模型可能对于开发新药以治疗充血性心力衰竭，这是美国的主要死亡原因。公共卫生相关性：泄漏的细胞内钙释放通道是心力衰竭收缩功能障碍的重要决定因素。我们将使用遗传小鼠模型来研究酶钙调蛋白依赖性激酶如何调节健康和失败心脏中细胞内钙释放通道的活性。这些研究可能有助于开发新的药理学方法来治疗心力衰竭，这是美国的主要死亡原因。