Crosstalk Ca2+ Signaling between Ryanodine Receptors Type 1 and 2 in the Pathogenesis of Cardiac Hypertrophy and Heart Failure

心脏肥大和心力衰竭发病机制中 1 型和 2 型 Ryanodine 受体之间的串扰 Ca2 信号传导

• 批准号: 10660636
• 负责人: Shey-Shing Sheu
• 金额: $ 58.24万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660636
• 关键词: Accounting; Animals; Arrhythmia; Bioenergetics; Cardiac; Cardiac Myocytes; Cell Death; Cells; Cessation of life; Chronic; Citric Acid Cycle; Compensation; Coupled; Coupling; Dantrolene; Data; Defect; Development; Electron Transport Complex III; Endothelin-1; Energy consumption; Enzymes; Frequencies; Functional disorder; Generations; Genetic; Heart; Heart Hypertrophy; Heart failure; Human; ITPR1 gene; In Vitro; Injury; Inositol; Iron; Knock-out; Knockout Mice; Knowledge; Lead; Malignant hyperpyrexia due to anesthesia; Mediating; Mitochondria; Molecular; Mus; Muscle Cells; Natural regeneration; Organ; Outcomes Research; Oxidative Stress; Paper; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Play; Process; Production; Proteins; Publishing; Pump; Regulation; Reporting; Research; Rieske iron-sulfur protein; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction; Stimulus; Stress; Sulfur; Therapeutic; Thoracic aorta; Tissue Sample; Up-Regulation; aorta constriction; effective therapy; energy balance; heart function; in vivo; inhibitor; innovation; insight; mitochondrial dysfunction; mitochondrial permeability transition pore; mortality; mouse model; novel; novel therapeutic intervention; overexpression; receptor; tool; tripolyphosphate; uptake

The underlying molecular mechanisms for heart failure (HF) are multifactorial, with energy dysregulation and oxidative stress appearing to be the key causes. The well-balanced energy consumption/generation of the working heart is thought to be achieved by Ca2+ entry via mitochondrial Ca2+ uniporter (MCU) which stimulates enzymes in the tricarboxylic acid (TCA) cycle for ATP generation, referred to as excitation-bioenergetics (EB) coupling. Surprisingly, knockout of MCU in the heart results in minimal defects in bioenergetics, suggesting that other Ca2+ transporters also may participate in EB coupling. We have previously shown that ryanodine receptor type 1 (RyR1) is expressed in cardiac mitochondria (mRyR1), playing a key role in EB coupling. Several groups have confirmed our findings, including recent reports showing that Ca2+ release from the sarcoplasmic reticulum (SR) is tunneled to mRyR to stimulate ATP production. We have also obtained new data showing that RyR1 expression is increased in mouse and human hypertrophied heart. The mitochondria isolated from RyR1 over expression (OE) mouse hearts have higher Ca2+ concentrations ([Ca2+]m) and increased ROS generation. This RyR1 OE mouse also shows cardiac hypertrophy and higher frequency of Ca2+ sparks, suggesting leakier RyR2 for Ca2+. Taken together, we propose a novel central hypothesis: Hypertrophic stimuli lead to mRyR1 overexpression in heart to compensate for increased energy demands by promoting mitochondrial Ca2+ uptake for EB coupling (Aim 1). However, chronic increases in mitochondrial Ca2+ uptake causes a sustained high level of ROS generation via Rieske iron-sulfur protein (RISP) at complex III (Aim 2). The increased ROS would oxidize and thus activate nearby SR RyR2 further increase mitochondrial Ca2+ loading due to constant Ca2+ leak from SR. This vicious cycle of ↑mRyR1→↑[Ca2+]m→↑ROS→↑SR RyR2 Ca2+ leak→↑[Ca2+]m (→: leads to, ↑: increases), which causes mitochondrial dysfunction including opening of mitochondrial permeability transition pore. Consequently, the heart is failing because of the inadequate energy for pumping and higher myocyte death and injury (Aim 3). The successful research outcome from this proposal will provide a new paradigm for HF: that RyR1 OE in the stressed heart is an initial adaptive mechanism that sequentially become mal-adaptive, which subsequently leads to HF. This new information will highlight a potentially innovative therapeutic strategy for development of novel inhibitors that are more selective for RyR1 than for RyR2 – such as dantrolene which has already been frequently used for treating malignant hyperthermia patients – as effective treatments of cardiac hypertrophy and HF.

心力衰竭（HF）的基本分子机制是多因素的，具有能量 失调和氧化应激似乎是关键原因。平衡的能量 人们认为，通过CA2+进入可以实现工作心脏的消费/产生 线粒体Ca2+静电蛋白（MCU）刺激三核酸（TCA）中的酶 ATP生成的周期，称为兴奋生物能力（EB）耦合。出奇， 心脏中MCU的敲除导致生物能的最小缺陷，这表明其他 CA2+转运蛋白也可能参与EB耦合。我们以前已经表明ryanodine 受体1型（RYR1）在心脏线粒体（MRYR1）中表达，在EB中起关键作用 耦合。几个小组已经确认了我们的发现，包括最近的报告表明CA2+ 从肌质网（SR）释放到Mryr隧道以刺激ATP产生。 我们还获得了新数据，表明小鼠和人类中的RYR1表达增加 肥大的心。从RYR1分离出表达（OE）小鼠心脏的线粒体 具有较高的Ca2+浓度（[Ca2+] M）和增加的ROS产生。这款RYR1 OE鼠标 还显示了Ca2+火花的心脏肥大和较高的频率，这表明Leafier Ryr2 对于Ca2+。综上所述，我们提出了一个新的中心假设：肥大刺激导致 MRYR1心脏中的过表达，以促进增加能源需求 线粒体Ca2+ EB耦合的吸收（AIM 1）。但是，线粒体的慢性增加 Ca2+摄取可通过Rieske Iron-Sulfur蛋白（RISP）引起持续的高水平ROS生成 在复合体III（AIM 2）。增加的ROS会氧化物，从而激活附近的SR RYR2 由于恒定的Ca2+ SR泄漏而导致的线粒体Ca2+负载进一步增加。这个恶性循环 ↑mryr1→↑[Ca2+] m→↑ROS→↑SR RYR2 CA2+泄漏→↑[Ca2+] M（→：导致，↑：增加）， 导致线粒体功能障碍，包括打开线粒体通透性过渡孔。 因此，由于抽水和更高的能量不足，心脏正在失败 心肌死亡和伤害（AIM 3）。该提议的成功研究结果将 为HF提供新的范式：压力心脏中的RyR1 OE是最初的自适应 依次变为MAL自适应的机制，随后导致HF。这个新 信息将突出一个潜在的创新理论策略，以发展新颖 对RYR1比RYR2更具选择性的抑制剂 - 例如Dantrolene 经常用于治疗恶性高温患者 - 作为有效治疗 心脏肥大和HF。