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 [J].
Agah, R ;
Frenkel, PA ;
French, BA ;
Michael, LH ;
Overbeek, PA ;
Schneider, MD .
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 [J].
Bergmann, MW ;
Loser, P ;
Dietz, R ;
von Harsdorf, R .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2001, 33 (06) :1223-1232
[3]   Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice [J].
Bueno, OF ;
Wilkins, BJ ;
Tymitz, KM ;
Glascock, BJ ;
Kimball, TF ;
Lorenz, JN ;
Molkentin, JD .
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 [J].
Clerk, A ;
Pham, FH ;
Fuller, SJ ;
Sahai, E ;
Aktories, K ;
Marais, R ;
Marshall, C ;
Sugden, PH .
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 [J].
Craig, R ;
Wagner, M ;
McCardle, T ;
Craig, AG ;
Glembotski, CC .
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 [J].
Dawn, B ;
Xuan, YT ;
Marian, M ;
Flaherty, MP ;
Murphree, SS ;
Smith, TL ;
Bolli, R ;
Jones, WK .
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 [J].
De Keulenaer, GW ;
Wang, YL ;
Feng, YJ ;
Muangman, S ;
Yamamoto, K ;
Thompson, JF ;
Turi, TG ;
Landschutz, K ;
Lee, RT .
CIRCULATION RESEARCH, 2002, 90 (06) :690-696
[8]   Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo [J].
De Windt, LJ ;
Lim, HW ;
Bueno, OF ;
Liang, QR ;
Delling, U ;
Braz, JC ;
Glascock, BJ ;
Kimball, TF ;
del Monte, F ;
Hajjar, RJ ;
Molkentin, JD .
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 [J].
Ding, B ;
Price, RL ;
Borg, TK ;
Weinberg, EO ;
Halloran, PF ;
Lorell, BH .
CIRCULATION RESEARCH, 1999, 84 (06) :729-734