OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-κB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-κB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-κB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion. METHODS AND RESULTS: Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 μg/kg per min) for 6 days increased LV NF-κB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-κB inhibitor, abolished Ang II-induced NF-κB activation and concomitant increase in tumor necrosis factor-α gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-κB 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 μg/kg per min) was not associated with a significant activation of NF-κB, and PDTC treatment had no effect on the hypertrophic indices. CONCLUSION: Our in-vivo data indicate a critical role of NF-κB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-κB activation.
- Angiotensin II
- Nuclear factor-κB
ASJC Scopus subject areas
- Internal Medicine
- Cardiology and Cardiovascular Medicine