Development of novel therapeutic strategy for heart failure which targets aberrant phosphorylation status in the sarcoplasmic reticulum of failing hearts

靶向Ca^<2+>循环已成为治疗严重心力衰竭的潜在疗法。这些方法包括针对过表达肌浆网（SR）Ca^2+> ATP_ase的基因治疗，或消除受磷蛋白（PLN）和相关蛋白磷酸酶1（PP 1）蛋白复合物。我们以前报道过，PP 1是PP 1的催化亚基之一，在三种PP 1亚型中，PP 1主要抑制SR中的Ca^2+摄取，从而促进衰竭心脏中Ca^2+的下调。在本研究中，我们研究了通过腺相关病毒-9（AAV 9）载体介导的基因治疗对心力衰竭诱导的PP 1抑制是否有利于预防遗传性心肌病小鼠的疾病进展。在MLPKO小鼠中，诱导型PP 1 shRNA递送优先改善左心室舒张功能并减轻不利的心室重构。心力衰竭诱导的PP 1分子靶向治疗有可能成为心力衰竭的一种新的治疗策略。

The targeting of Ca^<2+> cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum(SR) Ca^<2+> ATP_ase, or ablation of phospholamban(PLN) and associated protein phosphatase 1(PP1) protein complexes. We previously reported that PP1, one of the PP1 catalytic subunits, predominantly suppresses Ca^<2+> uptake in the SR among the three PP1 isoforms, thereby contributing to Ca^<2+> downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1-inhibition by adeno-associated viral-9(AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice. In the MLPKO mice, inducible PP1shRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. Heart failure-inducible molecular targeting of PP1 has potential as a novel therapeutic strategy for heart failure.