Abstract
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.
Highlights
Atrial fibrillation (AF) progresses from rare paroxysmal episodes, often unrecognized by patients, to long-lasting persistent and permanent stages [1]
Mean values of RR-intervals and thereby heart rate remained unchanged over the entire observation period, calculation of heart rate variability revealed a non-significant trend of increased heart rate variabilities by about 30% in Jun dimerization protein 2 (JDP2) mice (n = 6–11, n.s. vs. WT, Table 1)
Prolongation of PQ-intervals and QRS-complexes were observed after 2 weeks and prolonged JDP2 overexpression, reaching levels of 35.1 ± 3.6 ms in JDP2 mice vs. 30.3 ± 7.0 ms in WT for PQ-intervals, 11.6 ± 1.1 ms in JDP2 mice vs. 10.0 ± 1.5 ms in WT for P-wave duration (n = 10–11, p < 0.05), and 15.8 ± 2.3 ms in JDP2 mice vs. 13.9 ± 1.7 ms in WT for QRS-complexes (n = 10–11, p < 0.05) after 5 weeks of JDP2 overexpression (Figure 1A, Table 1)
Summary
Atrial fibrillation (AF) progresses from rare paroxysmal episodes, often unrecognized by patients, to long-lasting persistent and permanent stages [1]. Spontaneous sarcoplasmic reticulum (SR) calcium release via altered RyR2 may serve as a trigger for AF, with reduced APD, impaired conduction and increased fibrosis serving as substrates that promote the reentry and maintenance of AF The mechanisms underlying this extensive atrial remodeling are not fully understood. Very recently in our own studies on JDP2 mice, we were able to confirm atrial dilatation after 5 weeks of JDP2 overexpression [9] These data gave us reason to analyze the development of conduction defects and AF in closer detail in JDP2 mice, and to characterize JDP2 mice as an animal model that spontaneously develops AF. Electrocardiograms (ECGs) from awake mice indicate that JDP2 mice suffered from AF, the occurrence of which increased with increasing duration of JDP2 overexpression (from 1 to 5 weeks) Taken together, these data suggest a role of JPD2 in the development of a substrate for spontaneous onset of AF. Such research may reveal novel, truly effective targets for AF therapy and prevention
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