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Published on: June 29, 2022
Structural, Pro-Inflammatory and Calcium Handling Remodeling Underlies Spontaneous Onset of Paroxysmal Atrial
Mariana S Parahuleva1, Jens Kockskämper2, Jacqueline Heger3
1Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, 35033 Marburg, Germany.
Background:
Cardiac-specific JDP2 overexpression provokes ventricular dysfunction and atrial dilatation in mice. We performed in vivo studies on JDP2-overexpressing mice to investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF).
Methods:
JDP2-overexpression was started by withdrawal of a doxycycline diet in 4-week-old mice. The spontaneous onset of AF was documented by ECG within 4 to 5 weeks of JDP2 overexpression. Gene expression was analyzed by real-time RT-PCR and Western blots.
Results:
In atrial tissue of JDP2 mice, besides the 3.6-fold increase of JDP2 mRNA, no changes could be detected within one week of JDP2 overexpression. Atrial dilatation and hypertrophy, combined with elongated cardiomyocytes and fibrosis, became evident after 5 weeks of JDP2 overexpression. Electrocardiogram (ECG) recordings revealed prolonged PQ-intervals and broadened P-waves and QRS-complexes, as well as AV-blocks and paroxysmal AF. Furthermore, reductions were found in the atrial mRNA and protein level of the calcium-handling proteins NCX, Cav1.2 and RyR2, as well as of connexin40 mRNA. mRNA of the hypertrophic marker gene ANP, pro-inflammatory MCP1, as well as markers of immune cell infiltration (CD68, CD20) were increased in JDP2 mice.
Conclusion:
JDP2 is an important regulator of atrial calcium and immune homeostasis and is involved in the development of atrial conduction defects and arrhythmogenic substrates preceding paroxysmal AF.
Insights
Overexpressing JDP2 in mice leads to atrial remodeling and conduction defects, promoting spontaneous atrial fibrillation (AF). This study reveals JDP2
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Cardiac-specific JDP2 overexpression causes ventricular dysfunction and atrial dilatation in mice.
- Investigating the role of JDP2 in atrial fibrillation (AF) predisposition is crucial.
Purpose of the Study:
- To investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF) in vivo.
- To understand JDP2's role in atrial remodeling and cardiac function.
Main Methods:
- JDP2 overexpression induced by doxycycline withdrawal in 4-week-old mice.
- Spontaneous AF onset monitored by ECG within 4-5 weeks.
- Gene expression analyzed via real-time RT-PCR and Western blots.
Main Results:
- JDP2 overexpression led to atrial dilatation, hypertrophy, cardiomyocyte elongation, and fibrosis after 5 weeks.
- ECG revealed prolonged PQ-intervals, broadened P-waves/QRS-complexes, AV-blocks, and paroxysmal AF.
- Reduced atrial expression of calcium-handling proteins (NCX, Cav1.2, RyR2) and connexin40; increased ANP, MCP1, CD68, and CD20 mRNA.
Conclusions:
- JDP2 is a key regulator of atrial calcium and immune homeostasis.
- JDP2 contributes to atrial conduction defects and arrhythmogenic substrates.
- JDP2 plays a significant role in the development of paroxysmal atrial fibrillation.
