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Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis
- Source :
- JCI Insight. 4
- Publication Year :
- 2019
- Publisher :
- American Society for Clinical Investigation, 2019.
-
Abstract
- Atrial dysfunction is highly prevalent and associated with increased severity of heart failure. While rapid excitation-contraction coupling depends on axial junctions in atrial myocytes, the molecular basis of atrial loss of function remains unclear. We identified approximately 5-fold lower junctophilin-2 levels in atrial compared with ventricular tissue in mouse and human hearts. In atrial myocytes, this resulted in subcellular expression of large junctophilin-2 clusters at axial junctions, together with highly phosphorylated ryanodine receptor (RyR2) channels. To investigate the contribution of junctophilin-2 to atrial pathology in adult hearts, we developed a cardiomyocyte-selective junctophilin-2–knockdown model with 0 mortality. Junctophilin-2 knockdown in mice disrupted atrial RyR2 clustering and contractility without hypertrophy or interstitial fibrosis. In contrast, aortic pressure overload resulted in left atrial hypertrophy with decreased junctophilin-2 and RyR2 expression, disrupted axial junctions, and atrial fibrosis. Whereas pressure overload accrued atrial dysfunction and heart failure with 40% mortality, additional junctophilin-2 knockdown greatly exacerbated atrial dysfunction with 100% mortality. Strikingly, transgenic junctophilin-2 overexpression restored atrial contractility and survival through de novo biogenesis of polyadic junctional membrane complexes maintained after pressure overload. Our data show a central role of junctophilin-2 cluster disruption in atrial hypertrophy and identify transgenic augmentation of junctophilin-2 as a disease-mitigating rationale to improve atrial dysfunction and prevent heart failure deterioration.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Junctional membrane complex
Muscle Proteins
Ryanodine receptor 2
Muscle hypertrophy
Contractility
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
Atrial Fibrillation
medicine
Animals
Humans
Heart Atria
cardiovascular diseases
Heart Failure
Pressure overload
business.industry
Ryanodine receptor
Myocardium
Membrane Proteins
Ryanodine Receptor Calcium Release Channel
General Medicine
medicine.disease
Sarcoplasmic Reticulum
Intercellular Junctions
030104 developmental biology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Heart failure
cardiovascular system
Cardiology
Aortic pressure
Female
business
Research Article
Subjects
Details
- ISSN :
- 23793708
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....bf241a117938cecda2869448bea297ee