Abstract：
Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.
摘要：
冠心病(CHD)是一种普遍的心脏病,在美国每年导致超过370,000人死亡。在冠心病中,冠状动脉闭塞导致心肌缺血，导致心肌梗死（MI）。Junctophilin-2（JPH2）是一种膜蛋白，可确保有效的钙处理和适当的激发-收缩偶联。研究已经确定由于钙蛋白酶介导的蛋白水解导致的JPH2的损失是缺血诱导的心力衰竭(HF)中的关键致病事件。我们的发现表明，钙蛋白酶2介导的JPH2裂解在缺血性心肌病患者和实验性MI小鼠中产生C末端裂解肽（JPH2-CTP）的水平增加。我们通过去除残基479-SPAGTPPQ-486以防止钙蛋白酶-2介导的在该位点的切割,创建了一种新的敲入小鼠模型。切割位点缺失（CSD）小鼠MI后心脏功能的功能和分子评估显示保留的心脏收缩力和减少的扩张，降低JPH2-CTP水平，减轻不良重塑，改进的T型管结构，和归一化SRCa2+处理。腺病毒介导的钙蛋白酶-2敲低在小鼠中表现出相似的发现。CTP的下拉，然后进行蛋白质组学分析，揭示了含有valosin的蛋白质（VCP）和BAG家族分子伴侣调节因子3（BAG3）是JPH2的新型结合伴侣。一起,我们的研究结果表明,阻断calpain-2介导的JPH2裂解可能是延缓MI后HF发展的有前景的新策略.
