Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1‐mediated calcium entry in heart failure
| Autor: | Andriy E. Belevych, Stephen Baine, Andrei V. Stepanov, Sandor Gyorke, Lisa E. Dorn, Ingrid M. Bonilla, Cynthia A. Carnes, Radmila Terentyeva, Dmitry Terentyev, Federica Accornero |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiac function curve Male medicine.medical_specialty STIM1 Ryanodine receptor 2 Muscle hypertrophy 03 medical and health sciences Mice 0302 clinical medicine Internal medicine medicine Myocyte echocardiography Animals Stromal Interaction Molecule 1 Pyridostigmine Pressure overload Heart Failure Ejection fraction calcium Ryanodine receptor Chemistry phosphorylation RyR2 Arrhythmias Cardiac Ryanodine Receptor Calcium Release Channel Cell Biology Original Articles medicine.disease excitation contraction coupling Mice Inbred C57BL 030104 developmental biology Endocrinology autonomics 030220 oncology & carcinogenesis Heart failure Molecular Medicine Original Article Cholinesterase Inhibitors hypertrophy Pyridostigmine Bromide |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text