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

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&agr;, 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.

[1]  Fatima Mechta-Grigoriou,et al.  JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress , 2004, Cell.

[2]  Michael D. Schneider,et al.  Signal Transducer and Activator of Transcription 3 Is Required for Myocardial Capillary Growth, Control of Interstitial Matrix Deposition, and Heart Protection From Ischemic Injury , 2004, Circulation research.

[3]  H. Drexler,et al.  Regulation of Proangiogenic Factor CCN1 in Cardiac Muscle: Impact of Ischemia, Pressure Overload, and Neurohumoral Activation , 2004, Circulation.

[4]  Claudio Napoli,et al.  Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia , 2004, Circulation.

[5]  D. Harrison,et al.  Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma , 2004, Circulation.

[6]  Yibin Wang,et al.  Stress-activated MAP kinases in cardiac remodeling and heart failure; new insights from transgenic studies. , 2004, Trends in cardiovascular medicine.

[7]  H. Drexler,et al.  In-Vivo Electrophysiological Study in Mice with Chronic Anterior Myocardial Infarction , 2002, Journal of Interventional Cardiac Electrophysiology.

[8]  Gunnar Klein,et al.  Evaluation of left ventricular diastolic function by pulsed Doppler tissue imaging in mice. , 2003, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[9]  Lan Liu,et al.  JunD stabilization results in inhibition of normal intestinal epithelial cell growth through P21 after polyamine depletion. , 2002, Gastroenterology.

[10]  K. Webster,et al.  Gene and Cell Therapy for Heart Disease , 2002, IUBMB life.

[11]  A. Lichtenberg,et al.  Expression of CYR61, an Angiogenic Immediate Early Gene, in Arteriosclerosis and Its Regulation by Angiotensin II , 2002, Circulation.

[12]  M. Eriksson,et al.  Mitogen-activated Protein Kinases and Activator Protein 1 Are Required for Proliferation and Cardiomyocyte Differentiation of P19 Embryonal Carcinoma Cells* , 2002, The Journal of Biological Chemistry.

[13]  H. Wong,et al.  Absence of inducible nitric oxide synthase modulates early reperfusion‐induced NF‐κB and AP‐1 activation and enhances myocardial damage , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  H. Drexler,et al.  TNFα decreases αMHC expression by a NO mediated pathway: Role of E-box transcription factors for cardiomyocyte specific gene regulation , 2002 .

[15]  E. Wagner,et al.  JunB can substitute for Jun in mouse development and cell proliferation , 2002, Nature Genetics.

[16]  Shokei Kim,et al.  Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine , 2002, Hypertension.

[17]  H. Drexler,et al.  TNFalpha decreases alphaMHC expression by a NO mediated pathway: role of E-box transcription factors for cardiomyocyte specific gene regulation. , 2002, Cardiovascular research.

[18]  E. Shin,et al.  c-Jun N-terminal kinase is involved in motility of endothelial cell , 2001, Experimental & Molecular Medicine.

[19]  J. Díez,et al.  Cardiomyocyte Apoptotic Cell Death in Arterial Hypertension: Mechanisms and Potential Management , 2001, Hypertension.

[20]  H. Piper,et al.  Transcription activator protein 1 (AP‐1) mediates NO‐induced apoptosis of adult cardiomyocytes , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  M. Dickens,et al.  c-Jun N-terminal kinase-interacting protein 1 inhibits gene expression in response to hypertrophic agonists in neonatal rat ventricular myocytes. , 2001, The Biochemical journal.

[22]  P. Anversa,et al.  Oxidative Stress–Mediated Cardiac Cell Death Is a Major Determinant of Ventricular Dysfunction and Failure in Dog Dilated Cardiomyopathy , 2001, Circulation research.

[23]  M. Arthur,et al.  JunD Regulates Transcription of the Tissue Inhibitor of Metalloproteinases-1 and Interleukin-6 Genes in Activated Hepatic Stellate Cells* , 2001, The Journal of Biological Chemistry.

[24]  M. Pfeffer,et al.  Activation of Cardiac c-Jun NH2-Terminal Kinases and p38-Mitogen-Activated Protein Kinases With Abrupt Changes in Hemodynamic Load , 2001, Hypertension.

[25]  E. Wagner,et al.  AP-1 in mouse development and tumorigenesis , 2001, Oncogene.

[26]  Shokei Kim,et al.  Angiotensin blockade inhibits increased JNKs, AP-1 and NF- kappa B DNA-binding activities in myocardial infarcted rats. , 2001, Journal of molecular and cellular cardiology.

[27]  O. Eickelberg,et al.  Molecular mechanisms of TGF‐β antagonism by interferon γ and cyclosporine A in lung fibroblasts , 2001 .

[28]  O. Eickelberg,et al.  Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  J. Weitzman,et al.  JunD protects cells from p53-dependent senescence and apoptosis. , 2000, Molecular cell.

[30]  B. Lorell,et al.  Left ventricular hypertrophy: pathogenesis, detection, and prognosis. , 2000, Circulation.

[31]  J. Weitzman,et al.  Targeted disruption of the murine junD gene results in multiple defects in male reproductive function. , 2000, Development.

[32]  C. Vinson,et al.  Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element. , 1999, Blood.

[33]  M. Hamada,et al.  Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial banding. , 1999, Life sciences.

[34]  Willem Flameng,et al.  Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188 , 1999, Nature Medicine.

[35]  S. Edgar,et al.  Microvascular involvement in cardiac pathology. , 1998, Journal of molecular and cellular cardiology.

[36]  M. Nemer,et al.  The C-Terminal Domain of c-fos Is Required for Activation of an AP-1 Site Specific forjun-fos Heterodimers , 1998, Molecular and Cellular Biology.

[37]  H. Schunkert,et al.  Regulation of the rat atrial natriuretic peptide gene after acute imposition of left ventricular pressure overload. , 1997, Hypertension.

[38]  K. Chien,et al.  The MEKK-JNK Pathway Is Stimulated by α1-Adrenergic Receptor and Ras Activation and Is Associated with in Vitroand in Vivo Cardiac Hypertrophy* , 1997, The Journal of Biological Chemistry.

[39]  K. Soprano,et al.  Differential expression of c‐jun and junD in end‐stage human cardiomyopathy , 1997, Journal of cellular biochemistry.

[40]  M. Yaniv,et al.  Variations in Jun and Fos protein expression and AP-1 activity in cycling, resting and stimulated fibroblasts , 1997, Oncogene.

[41]  Masahiko Hibi,et al.  c-Jun Can Recruit JNK to Phosphorylate Dimerization Partners via Specific Docking Interactions , 1996, Cell.

[42]  P. Singal,et al.  Role of oxidative stress in transition of hypertrophy to heart failure. , 1996, Journal of the American College of Cardiology.

[43]  B. Slinker,et al.  Immediate-early gene responses to different cardiac loads in the ejecting rabbit left ventricle. , 1996, Journal of molecular and cellular cardiology.

[44]  H. Schunkert,et al.  Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding. , 1995, The Journal of clinical investigation.

[45]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.

[46]  M. Yaniv,et al.  Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras , 1994, Cell.

[47]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[48]  M. Yaniv,et al.  Overexpression of c-jun, junB, or junD affects cell growth differently. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[49]  D E Manyari,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.