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, 8 (1), 7647

JDP2 Overexpression Provokes Cardiac Dysfunction in Mice

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JDP2 Overexpression Provokes Cardiac Dysfunction in Mice

Jacqueline Heger et al. Sci Rep.

Abstract

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
(A) Experimental study design. JDP2-overexpressing mice were fed for four weeks with doxycycline (Dox). Then Dox-feeding was stopped and JDP2 was overexpressed for one or five weeks. Parameters related to cardiac performance were analysed. (B) Evaluation of JDP2 overexpression. mRNA expressions of JDP2 were evaluated. Data are means ± SD. *Differences from WT-animals with p ≤ 0.05, n = 8. Furthermore, JDP2 protein from 5 weeks overexpressing hearts was detected in western blots by HA antibodies. Vinculin was used as loading control.
Figure 2
Figure 2
Blood pressure is increased in JDP2 mice. Data are means ± SD. *Differences from WT animals with p ≤ 0.05, n = 15.
Figure 3
Figure 3
Atrial dilatation after 5 weeks of JDP2 overexpression. (A) Micrographs of hearts. (B) Echocardiography recordings. Atrial dimensions are indicated.
Figure 4
Figure 4
JDP2 overexpression impairs contractile function in ventricular cardiomyoycytes. Cardiomyocytes were isolated from mice one week after start of JDP2 overexpression and from age matched WT animals. Contractions were analysed at 2 Hz in absence or presence of 10 nM isoprenaline (ISO). Data are means ± SD of 100 cells from 4 independent culture preparations. *Differences between WT and JDP2 overexpressing cardiomyocytes with p ≤ 0.05.
Figure 5
Figure 5
Apoptosis and Hypertrophy increases in JDP2 mice. Hearts were extracted from mice five weeks after start of JDP2 overexpression and from age matched WT animals. Apoptosis was detected by TUNEL-assay (n = 5). As hypertrophic parameter HW to BW ratio was determined (n = 15–22). Data are means ± SD. *Differences from WT animals with p ≤ 0.05.
Figure 6
Figure 6
Fibrosis and MMP2 are enhanced in JDP2 mice. Hearts were extracted from mice five weeks after start of JDP2 overexpression and from age matched WT animals. (A) Fibrotic marker gene expression (n = 8). (B) Quantification of fibrotic area in percent to total tissue area (n = 6). (C) Tissue sections stained with azan dye reveal blue coloured fibrotic areas. (D) Densitometric analysis of MMP2 bands from zymograms (n = 7–12). (E) Representative zymogram. Data are means ± SD. *Differences from WT animals with p ≤ 0.05.

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