Requirement of Nuclear Factor-κB in Angiotensin II– and Isoproterenol-Induced Cardiac Hypertrophy In Vivo

Abstract

Background— In vitro experiments have proposed a role of nuclear factor-κB (NF-κB), 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-κB super-repressor IκBαΔN (ΔN MHC ) using the Cre/lox technique. ΔN 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, ×1.5±0.1 versus sham; ΔN MHC plus Ang II, ×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 β-myosin heavy chain and atrial natriuretic peptide in Ang II–treated ΔN 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-κB 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-κB response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-κB in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. Conclusions— These results indicate that targeted inhibition of NF-κB in cardiomyocytes in vivo is sufficient to impair Ang II– and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.