Journal article
Integrin β1D Deficiency-Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in ARVC
Circulation, Vol.141(18), pp.1477-1493
03/03/2020
DOI: 10.1161/CIRCULATIONAHA.119.043504
PMCID: PMC7200284
PMID: 32122157
Abstract
Background:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood.
Methods:
Using protein mass spectrometry analyses, we identified that integrin β1 is downregulated in ARVC hearts without changes to Ca2+-handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin β1D loss on function in the heart in vivo and in vitro.
Results:
Integrin β1D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, β1D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca2+ handling in β1D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin β1D deficiency in ARVC mediated through an ERK1/2 (extracellular signal–regulated kinase 1 and 2)–fibronectin–ubiquitin/lysosome pathway.
Conclusions:
Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.
Details
- Title: Subtitle
- Integrin β1D Deficiency-Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in ARVC
- Creators
- Yihui Wang - Peking Union Medical College HospitalLing ShiChunyan Li - Peking Union Medical College HospitalXiuyu Chen - Peking Union Medical College HospitalChen Cui - Peking Union Medical College HospitalJinhua Huang - Fujian Medical UniversityBiyi Chen - University of Iowa, Internal MedicineDuane D Hall - University of Iowa, Internal MedicineMinjie Lu - Peking Union Medical College HospitalZhenwei PanJiang Hong - Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai 200080, ChinaLong-Sheng Song - University of Iowa, Internal MedicineShihua Zhao - Peking Union Medical College Hospital
- Resource Type
- Journal article
- Publication Details
- Circulation, Vol.141(18), pp.1477-1493
- DOI
- 10.1161/CIRCULATIONAHA.119.043504
- PMID
- 32122157
- PMCID
- PMC7200284
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Copyright
- © 2020 American Heart Association, Inc
- Grant note
- This work was supported by China Key International Cooperation Projects of the National Natural Science Foundation of China, grant no. 81620108015 (S.H.Z.); Research on the Application of Clinical Characteristics in Capital Beijing, grant no. Z61100000516110 (S.H.Z); China Key International Cooperation Projects of the National Natural Science Foundation of China grant no. 81930044 (S.H.Z.); US National Institutes of Health, National Heart, Lung, Blood Institute grants HL090905 and HL130346; and US Department of Veterans Affairs grant no. I01-BX002334 (L.S.S.).
- Language
- English
- Date published
- 03/03/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9983790993102771
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