Requirement of nuclear factor-κB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo

被引:163
作者
Freund, C
Schmidt-Ullrich, R
Baurand, A
Dunger, S
Schneider, W
Loser, P
El-Jamali, A
Dietz, R
Scheidereit, C
Bergmann, MW
机构
[1] Franz Volhard Clin, Dept Cardiol, HELIOS Klinikum Berlin, D-13125 Berlin, Germany
[2] Robert Koch Inst, D-1000 Berlin, Germany
[3] Max Delbruck Ctr Mol Med, Berlin, Germany
关键词
angiotensin; genes; hypertrophy; myocytes; nuclear factor-kappa B;
D O I
10.1161/01.CIR.0000164237.58200.5A
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-In vitro experiments have proposed a role of nuclear factor-kappa B (NF-kappa B), a transcription factor, in cardiomyocyte hypertrophy and protection against apoptosis. Currently, the net effect on cardiac remodeling in vivo under common stress stimuli is unclear. Methods and Results-We have generated mice with cardiomyocyte-restricted expression of the NF-kappa B super-repressor I kappa B alpha Delta N (Delta N-MHC) using the Cre/lox technique. Delta N-MHC mice displayed an attenuated hypertrophic response compared with control mice on infusion of angiotensin II (Ang II) or isoproterenol by micro-osmotic pumps, as determined by echocardiography (left ventricular wall dimensions: control plus Ang II, x 1.5 +/- 0.1 versus sham; Delta N-MHC plus Ang II, x 1.1 +/- 0.1 versus sham; P < 0.05; n >= 9), heart weight, and histological analysis. Real-time reverse-transcriptase polymerase chain reaction showed significantly reduced expression of hypertrophy markers beta- myosin heavy chain and atrial natriuretic peptide in Ang II-treated Delta N-MHC mice (P < 0.05 versus control plus Ang II; n = 4). Neither cardiomyocyte apoptosis nor left ventricular dilatation was observed. In cultured adult rat cardiomyocytes, NF-kappa B DNA binding activity was increased by both Ang II- and interleukin-6-related cytokines. The latter are known to be released by cardiac fibroblasts on Ang II stimulation and thus could locally increase the NF-kappa B response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-kappa B in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. Conclusions-These results indicate that targeted inhibition of NF-kappa B in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.
引用
收藏
页码:2319 / 2325
页数:7
相关论文
共 28 条
  • [1] Gene recombination in postmitotic cells - Targeted expression of cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo
    Agah, R
    Frenkel, PA
    French, BA
    Michael, LH
    Overbeek, PA
    Schneider, MD
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (01) : 169 - 179
  • [2] Effect of NF-κB inhibition on TNF-α-induced apoptosis and downstream pathways in cardiomyocytes
    Bergmann, MW
    Loser, P
    Dietz, R
    von Harsdorf, R
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2001, 33 (06) : 1223 - 1232
  • [3] Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice
    Bueno, OF
    Wilkins, BJ
    Tymitz, KM
    Glascock, BJ
    Kimball, TF
    Lorenz, JN
    Molkentin, JD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (07) : 4586 - 4591
  • [4] Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1
    Clerk, A
    Pham, FH
    Fuller, SJ
    Sahai, E
    Aktories, K
    Marais, R
    Marshall, C
    Sugden, PH
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (04) : 1173 - 1184
  • [5] The cytoprotective effects of the glycoprotein 130 receptor-coupled cytokine, cardiotrophin-1, require activation of NF-κB
    Craig, R
    Wagner, M
    McCardle, T
    Craig, AG
    Glembotski, CC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (40) : 37621 - 37629
  • [6] Cardiac-specific abrogation of NF-κB activation in mice by transdominant expression of a mutant IκBα
    Dawn, B
    Xuan, YT
    Marian, M
    Flaherty, MP
    Murphree, SS
    Smith, TL
    Bolli, R
    Jones, WK
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2001, 33 (01) : 161 - 173
  • [7] Identification of IEX-1 as a biomechanically controlled nuclear factor-κB target gene that inhibits cardiomyocyte hypertrophy
    De Keulenaer, GW
    Wang, YL
    Feng, YJ
    Muangman, S
    Yamamoto, K
    Thompson, JF
    Turi, TG
    Landschutz, K
    Lee, RT
    [J]. CIRCULATION RESEARCH, 2002, 90 (06) : 690 - 696
  • [8] Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo
    De Windt, LJ
    Lim, HW
    Bueno, OF
    Liang, QR
    Delling, U
    Braz, JC
    Glascock, BJ
    Kimball, TF
    del Monte, F
    Hajjar, RJ
    Molkentin, JD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (06) : 3322 - 3327
  • [9] Demoulin JB, 1996, MOL CELL BIOL, V16, P4710
  • [10] Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin
    Ding, B
    Price, RL
    Borg, TK
    Weinberg, EO
    Halloran, PF
    Lorell, BH
    [J]. CIRCULATION RESEARCH, 1999, 84 (06) : 729 - 734