Targeted inhibition of NF-kappaB in cardiomyocytes in vivo significantly attenuated angiotensin II-induced left ventricular hypertrophy (wall dimensions x1.1 vs x1.5 in controls; P<0.05).
Does targeted inhibition of NF-kappaB in cardiomyocytes prevent Ang II- and isoproterenol-induced cardiac hypertrophy in vivo?
Targeted inhibition of NF-kappaB in cardiomyocytes in vivo impairs Ang II- and isoproterenol-induced hypertrophy without increasing susceptibility to apoptosis.
Absolute Event Rate: 1.1% vs 1.5%
p-value: p=<0.05
BACKGROUND: In vitro experiments have proposed a role of nuclear factor-kappaB (NF-kappaB), 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-kappaB super-repressor IkappaBalphaDeltaN (DeltaN(MHC)) using the Cre/lox technique. DeltaN(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, x1.5+/-0.1 versus sham; DeltaN(MHC) plus Ang II, x1.1+/-0.1 versus sham; P or =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 DeltaN(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-kappaB 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-kappaB response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-kappaB in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. CONCLUSIONS: These results indicate that targeted inhibition of NF-kappaB in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.
Freund et al. (Wed,) conducted a other in Cardiac hypertrophy. Cardiomyocyte-restricted expression of NF-kappaB super-repressor IkappaBalphaDeltaN vs. Control mice was evaluated on Hypertrophic response to angiotensin II (left ventricular wall dimensions fold change versus sham) (p=<0.05). Targeted inhibition of NF-kappaB in cardiomyocytes in vivo significantly attenuated angiotensin II-induced left ventricular hypertrophy (wall dimensions x1.1 vs x1.5 in controls; P<0.05).