Nuclear factor-kappaB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling.
OBJECTIVE
The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-kappaB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-kappaB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion.


RESULTS
Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 microg/kg per min) for 6 days increased LV NF-kappaB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-kappaB inhibitor, abolished Ang II-induced NF-kappaB activation and concomitant increase in tumor necrosis factor-alpha gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-kappaB signaling for 6 days significantly attenuated Ang II-induced increases in LV/body weight ratio, LV mean wall thickness and cardiomyocyte cross-sectional area, without compromising LV systolic function. Moreover, PDTC abolished Ang II-induced cardiomyocyte apoptosis and interstitial fibrosis, and attenuated the gene expression of type I collagen. In contrast, a moderate LV hypertrophy induced by Ang II at a lower dose (0.5 microg/kg per min) was not associated with a significant activation of NF-kappaB, and PDTC treatment had no effect on the hypertrophic indices.


CONCLUSIONS
Our in-vivo data indicate a critical role of NF-kappaB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-kappaB activation.
Sármán
Balázs
B
First Department of Medicine, Semmelweis University, Hungary.
Skoumal
Réka
R
Leskinen
Hanna
H
Rysä
Jaana
J
Ilves
Mika
M
Soini
Ylermi
Y
Tuukkanen
Juha
J
Pikkarainen
Sampsa
S
Lakó-Futó
Zoltán
Z
Sármán
Beatrix
B
Papp
Lajos
L
deChâtel
Rudolf
R
Tóth
Miklós
M
Ruskoaho
Heikki
H
Szokodi
István
I
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004452:Echocardiography; D024202:Electrophoretic Mobility Shift Assay; D006352:Heart Ventricles / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D017931:DNA Primers; D016328:NF-kappa B; D000804:Angiotensin II