Baine Stephen, Bonilla Ingrid, Belevych Andriy, Stepanov Andrei, Dorn Lisa E, Terentyeva Radmila, Terentyev Dmitry, Accornero Federica, Carnes Cynthia A, Gyorke Sandor
College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
J Cell Mol Med. 2021 May;25(10):4637-4648. doi: 10.1111/jcmm.16356. Epub 2021 Mar 23.
Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac function remain unclear. The present study examined the effects and underpinning mechanisms of chronic treatment with the cholinesterase inhibitor, pyridostigmine (PYR), in pressure overload HF induced by transverse aortic constriction (TAC) in mice. TAC mice exhibited characteristic adverse structural (left ventricular hypertrophy) and functional remodelling (reduced ejection fraction, altered myocyte calcium (Ca) handling, increased arrhythmogenesis) with enhanced predisposition to arrhythmogenic aberrant sarcoplasmic reticulum (SR) Ca release, cardiac ryanodine receptor (RyR2) hyper-phosphorylation and up-regulated store-operated Ca entry (SOCE). PYR treatment resulted in improved cardiac contractile performance and rhythmic activity relative to untreated TAC mice. Chronic PYR treatment inhibited altered intracellular Ca handling by alleviating aberrant Ca release and diminishing pathologically enhanced SOCE in TAC myocytes. At the molecular level, these PYR-induced changes in Ca handling were associated with reductions of pathologically enhanced phosphorylation of RyR2 serine-2814 and STIM1 expression in HF myocytes. These results suggest that chronic cholinergic augmentation alleviates HF via normalization of both canonical RyR2-mediated SR Ca release and non-canonical hypertrophic Ca signaling via STIM1-dependent SOCE.
心力衰竭（HF）的特征是自主神经平衡不对称。在人类心力衰竭试验中，恢复副交感神经活动的治疗已显示出有益效果。然而，副交感神经介导的心脏功能改善机制仍不清楚。本研究考察了胆碱酯酶抑制剂吡啶斯的明（PYR）长期治疗对小鼠主动脉缩窄（TAC）所致压力超负荷HF的影响及其潜在机制。TAC小鼠表现出典型的不良结构（左心室肥厚）和功能重塑（射血分数降低、心肌细胞钙（Ca）处理改变、心律失常发生率增加），且对致心律失常性异常肌浆网（SR）Ca释放、心脏雷诺丁受体（RyR2）过度磷酸化和上调的储存-操作性Ca内流（SOCE）的易感性增强。与未治疗的TAC小鼠相比，PYR治疗可改善心脏收缩性能和节律活动。长期PYR治疗通过减轻TAC心肌细胞中异常的Ca释放并减少病理性增强的SOCE，抑制了细胞内Ca处理的改变。在分子水平上，这些PYR诱导的Ca处理变化与HF心肌细胞中RyR2丝氨酸-2814病理性增强的磷酸化和STIM1表达的降低有关。这些结果表明，长期胆碱能增强通过使经典的RyR2介导的SR Ca释放和通过STIM1依赖性SOCE的非经典肥厚性Ca信号正常化来减轻HF。
