Institute of Physiology, Justus Liebig University, Giessen, Germany.
Department of Biochemistry, University of Szeged, Szeged, Hungary.
Sci Rep. 2018 May 16;8(1):7647. doi: 10.1038/s41598-018-26052-w.
The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.
转录调节因子 JDP2（Jun 二聚化蛋白 2）已被鉴定为心肌梗死后发生心力衰竭的患者的预后标志物。我们现在对 JDP2 过表达小鼠进行了体内研究，以阐明 JDP2 对心力衰竭进展的影响。因此，在转基因小鼠中，通过给予强力霉素喂养，从出生到 4 周龄期间阻止了心脏特异性 JDP2 的过表达。然后，开始 JDP2 的过表达。仅在 1 周后，通过超声心动图确定的心脏功能下降，这也反映在心肌细胞水平上。5 周后，血压下降，射血分数和心输出量减少，左心室扩张。心脏重量/体重比，以及 ANP、炎症标志物基因、胶原和纤维连接蛋白的 mRNA 表达增加。胶原 1 蛋白表达增加，纤维化发展。作为细胞外基质重塑增加的另一个迹象，JDP2 小鼠中的基质金属蛋白酶 2 活性增加。因此，JDP2 的过表达对体内心脏功能是有害的。可以得出结论，JDP2 的过表达会引起成年小鼠的心脏功能障碍，伴有肥大和纤维化。因此，JDP2 的诱导是导致心力衰竭发展的适应性反应。
