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) 的潜在分子机制是多因素的，其中能量 失调和氧化应激似乎是能量平衡的主要原因。 工作心脏的消耗/生成被认为是通过 Ca2+ 进入来实现的 线粒体 Ca2+ 单向转运蛋白 (MCU)，可刺激三羧酸 (TCA) 中的酶 ATP 生成的循环，称为激发-生物能学 (EB) 耦合。 敲除心脏中的 MCU 会导致生物能学方面的缺陷最小化，这表明其他 Ca2+ 转运蛋白也可能参与 EB 偶联 我们之前已经证明了兰尼定。 1 型受体 (RyR1) 在心脏线粒体 (mRyR1) 中表达，在 EB 中发挥关键作用 几个小组已经证实了我们的发现，包括最近的报告显示 Ca2+。 肌浆网 (SR) 的释放通过隧道传输至 mRyR 以刺激 ATP 产生。 我们还获得了新数据，表明 RyR1 表达在小鼠和人类中增加 从 RyR1 过度表达 (OE) 小鼠心脏中分离出的线粒体。 该 RyR1 OE 小鼠具有更高的 Ca2+ 浓度 ([Ca2+]m) 和更多的 ROS 生成。 还显示心脏肥大和 Ca2+ 火花频率更高，表明 RyR2 泄漏 综上所述，我们提出了一个新的中心假设：肥大刺激导致 mRyR1 在心脏中过度表达，通过促进 EB 偶联的线粒体 Ca2+ 摄取（目标 1）。 Ca2+ 吸收通过 Rieske 铁硫蛋白 (RISP) 导致持续高水平的 ROS 生成 在复合物 III 处（目标 2），增加的 ROS 会氧化，从而激活附近的 SR RyR2。 由于 SR 中 Ca2+ 不断泄漏，进一步增加线粒体 Ca2+ 负载，这种恶性循环。 ↑mRyR1→↑[Ca2+]m→↑ROS→↑SR RyR2 Ca2+ 泄漏→↑[Ca2+]m（→：导致，↑：增加），其中 导致线粒体功能障碍，包括线粒体通透性转换孔的开放。 检查发现，心脏由于泵血能量不足和更高的压力而衰竭。 心肌细胞死亡和损伤（目标 3）。 为 HF 提供了一个新的范例：RyR1 OE 在应激心脏中是一种初始适应性 机制逐渐变得不适应，从而导致心力衰竭。 信息将强调开发新药物的潜在创新治疗策略 对 RyR1 比对 RyR2 更具选择性的抑制剂 – 例如 dantrolene，它已经 经常用于治疗恶性高热患者——作为治疗的有效疗法 心脏肥大和心力衰竭。