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

Abstract

Background-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. Methods and Results-Mice lacking JunD (knockout [KO]) showed increased mortality and enhanced cardiomyocyte apoptosis and fibrosis associated with increased levels of hypoxia-induced factor-1␣, 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. Conclusions-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.

Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload

“…Consistent with previous results, 29,30 TAC led to a 2.9-fold (PϽ0.01) increase in VEGF-A transcript expression ( Figure 1A). To investigate the links between coronary vasculature and compensatory cardiac hypertrophy, an adenoviral vector encoding a decoy VEGF receptor fused to the Fc fragment of IgG2a (Ad-Flk) or a control vector expressing only the Fc fragment (Ad-cont) was delivered to mice, and hearts were subjected to sham surgery or pressure overload resulting from TAC.…”

“…Previous studies have shown that VEGF is upregulated in myocardium in pathological conditions such as myocardial infarction, 31,32 pressure overload, 29,30 and hemodynamic overload. 33 In vitro, it has been shown that VEGF is secreted from cardiomyocytes in response to various extracellular stimuli.…”

Multiple facets of junD gene expression are atypical among AP-1 family members

“…Accordingly, JunD generally is considered to be a negative regulator of cell proliferation. For instance, JunD exhibits a cell-dependent role in apoptosis and prevents cell death in adult mouse heart cells (Hilfiker-Kleiner et al, 2005) and in UV/H 2 O 2 -stressed mouse embryonic fibroblasts (Zhou et al, 2007), while enhancing UV-induced increases in caspase-3 activity and apoptosis in human myeloblastic leukemia ML-1 cells (Li et al, 2002b). Given its pivotal role in balancing cell proliferation, differentiation and apoptosis, and the association of JunD dysregulation with several neoplasms and metabolic diseases, JunD is an attractive target molecule for therapeutic intervention.…”

Cardiac-specific overexpression of E40K active Akt prevents pressure overload-induced heart failure in mice by increasing angiogenesis and reducing apoptosis

“…We found that Akt ameliorates cardiac function by decreasing apoptosis and fibrosis and improving angiogenesis. We quantified capillaries in histological sections of hearts stained with FITC-conjugated lectin 8 ( Figure 1d, top). Under basal conditions, vascularization of Tg mouse myocardium was 1.8070.15 capillaries/CMC as compared to 1.1570.18 capillaries/CMC in WT controls (Figure 1d, bottom).…”