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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    ABSTRACT: Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hypertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.
    PLoS ONE 09/2013; 8(9):e73294. DOI:10.1371/journal.pone.0073294 · 3.23 Impact Factor
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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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    ABSTRACT: Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1) is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box-like and WD40 repeats-containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1) and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration.
    PLoS ONE 05/2012; 7(5):e37028. DOI:10.1371/journal.pone.0037028 · 3.23 Impact Factor
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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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    ABSTRACT: Exogenous stem cell delivery is under investigation to prevent and treat cardiac dysfunction. It is less studied as to the extent endogenous bone marrow derived stem cells contribute to cardiac homeostais in response to stress and the affects of aging on this stress response. To determine the role of bone marrow (BM) derived stem cells on cardiac homeostasis in response to pressure overload (PO) and how this response is altered by aging. Young (8 weeks) and old (>40 weeks) C57/b6 mice underwent homo- and heterochronic BM transplantation prior to transverse aortic constriction (TAC). We found that older BM is associated with decreased cardiac function following TAC. This decreased function is associated with decrease in BM cell engraftment, increased myocyte apoptosis, decreased myocyte hypertrophy, increased myocardial fibrosis and decreased cardiac function. Additionally, there is a decrease in activation of resident cells within the heart in response to PO in old mice. Interestingly, these effects are not due to alterations in vascular density or inflammation in response to PO or differences in ex vivo stem cell migration between young and old mice. BM derived stem cells are activated in response to cardiac PO, and the recruitment of BM derived cells are involved in cardiac myocyte hypertrophy and maintenance of function in response to PO which is lost with aging.
    PLoS ONE 12/2010; 5(12):e15187. DOI:10.1371/journal.pone.0015187 · 3.23 Impact Factor
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