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

心力衰竭（HF）的潜在分子机制是多因素的， 失调和氧化应激似乎是关键原因。平衡的能量 工作心脏的消耗/产生被认为是通过Ca 2+经由 线粒体Ca 2+单向转运体（MCU），其刺激三羧酸（TCA）中的酶 ATP生成的循环，称为激发-生物能量学（EB）偶联。令人惊奇的是， 心脏中MCU的敲除导致生物能量学的最小缺陷，这表明其他 Ca ~（2+）转运蛋白也可能参与EB偶联。我们之前已经证明， 1型受体（RyR 1）在心肌线粒体（mRyR 1）中表达，在EB中起关键作用 偶合器.几个研究小组已经证实了我们的发现，包括最近的报告表明，钙离子 从肌浆网（SR）释放的ATP通过隧道到达mRyR以刺激ATP产生。 我们还获得了新的数据，表明RyR 1表达在小鼠和人类中增加， 心脏肥大从RyR 1过表达（OE）小鼠心脏分离的线粒体 具有较高的Ca 2+浓度（[Ca 2 +]m）和增加的ROS产生。RyR 1 OE小鼠 也显示心脏肥大和更高频率的Ca 2+火花，表明RyR 2更渗漏 Ca2+。综上所述，我们提出了一个新的中心假设：肥大刺激导致 mRyR 1在心脏中的过表达通过促进增加的能量需求来补偿增加的能量需求 线粒体Ca 2+摄取用于EB偶联（Aim 1）。然而，线粒体的慢性增加 Ca 2+摄取通过Rieske铁硫蛋白（RISP）引起持续高水平的ROS产生 复合物III（目标2）。增加的ROS会氧化，从而激活附近的SR RyR 2 进一步增加线粒体Ca 2+负荷，这是由于SR的恒定Ca 2+泄漏。 ↑ mRyR 1 →↑[Ca 2 +]m→↑ROS→↑SR RyR 2 Ca 2+漏→↑[Ca 2 +]m（→：导致，↑：增加）， 导致线粒体功能障碍，包括线粒体通透性转换孔的开放。 因此，由于泵送和更高的能量不足，心脏正在衰竭。 心肌细胞死亡和损伤（目的3）。该提案的成功研究成果将 为HF提供了一个新的范例：应激心脏中的RyR 1 OE是一种初始的适应性调节因子， 随后变得适应不良的机制，其随后导致HF。这个新 信息将强调开发新型药物的潜在创新治疗策略 对RyR 1比对RyR 2更有选择性的抑制剂，如丹曲林， 经常用于治疗恶性高热患者-作为 心脏肥大和HF。

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.