Structural, Pro-Inflammatory and Calcium Handling Remodeling Underlies Spontaneous Onset of Paroxysmal Atrial Fibrillation in JDP2-Overexpressing Mice

International Journal of Molecular Sciences

Anna Scherer¹  Jens Kockskämper¹  Sarah Bühler¹  Jacqueline Heger²  Gerhild Euler²  Rainer Schulz²  MarianaS. Parahuleva³  Wolfram Grimm³  Julian Kreutz³ 

[1] Biochemical-Pharmacological Centre (BPC) Marburg, Institute of Pharmacology and Clinical Pharmacy, University of Marburg, 35043 Marburg, Germany;Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany;Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, 35033 Marburg, Germany;

关键词: JDP2;    atrial fibrillation;    atrial remodeling;    inflammation;    calcium-handling proteins;   

DOI  :  10.3390/ijms21239095

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown