Lack of JunD Promotes Pressure Overload-Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Circulation (Impact Factor: 14.43). 10/2005; 112(10):1470-7. DOI: 10.1161/CIRCULATIONAHA.104.518472
Source: PubMed


The Jun family of activator protein 1 (AP-1) transcription factors (c-Jun, JunB, and JunD) is involved in fundamental biological processes such as proliferation, apoptosis, tumor angiogenesis, and hypertrophy. The role of individual AP-1 transcription factors in the stressed heart is not clear. In the present study we analyzed the role of JunD in survival, hypertrophy, and angiogenesis in the pressure-overloaded mouse heart after thoracic aortic constriction.
Mice lacking JunD (knockout [KO]) showed increased mortality and enhanced cardiomyocyte apoptosis and fibrosis associated with increased levels of hypoxia-induced factor-1alpha, vascular endothelial growth factor (VEGF), p53, and Bax protein and reduced levels of Bcl-2 protein after 7 days of severe pressure overload compared with wild-type (WT) siblings. Cardiomyocyte hypertrophy in surviving KO mice was enhanced compared with that in WT mice. Chronic moderate pressure overload for 12 weeks caused enhanced left ventricular hypertrophy in KO mice, and survival and interstitial fibrosis were comparable with WT mice. Cardiac function, 12 weeks after operation, was comparable among shams and pressure-overloaded mice of both genotypes. In addition, KO mice exposed to chronic pressure overload showed higher cardiac capillary density associated with increased protein levels of VEGF.
Thus, JunD limits cardiomyocyte hypertrophy and protects the pressure-overloaded heart from cardiac apoptosis. These beneficial effects of JunD, however, are associated with antiangiogenic properties.

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    • "Early-immediate up-regulation of AP-1 in response to cardiac hypertrophic stimuli has been reported already in nineties [20]–[23]. But only recently, first evidence for a requirement of AP-1 in the adult heart in vivo has been provided using mice that lack and/or ectopically express junD and fra-1, respectively [24], [25]. Preceding in vitro studies have mainly focused on the role of c-jun and c-fos in cardiomyocyte growth, two principal factors that are activated by JNK and ERK, respectively. "
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    • "Many molecules regulate the expression of apoptosis-related genes in cells. Notably, mice lacking junD show enhanced levels of Bax and p53, suggesting that AP-1 is a key regulatory molecule for maintaining low expression of apoptosis-related genes [41]. Our mosaic analysis using third instar larval eye discs showed that hid expression was increased in ebi mutant clones, suggesting that the Ebi/AP-1 repression system may be involved in regulating the basal expression level of the pro-apoptotic gene hid in sensory neurons (Figure 4C). "
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    Preview · Article · May 2012 · PLoS ONE
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    • "For vessel quantification and myocyte density, sections were incubated with fluorescein-conjugated isolectin (Vector Laboratories), labeling endothelium and rhodamine-conjugated wheat germ agglutinin (Vector Laboratories), which labels myocyte membranes as previously described [21]. Five randomly chosen cross-sectional fields for each sample were imaged at 400× using confocal microscopy (Leica). "
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