Abstract 1626: Nuclear Transcription Factor-Kappa B Contributes To Neurohumoral Excitation In Heart Failure
Nuclear Factor-kappa B (NFκB) is a redox sensitive transcription factor that is activated in response to various inflammatory processes including heart failure. Previous studies from our lab suggest that the pro-inflammatory cytokines (PIC), reactive oxygen species (ROS) and angiotensin II receptor-type 1 (AT-1R) in the paraventricular nucleus (PVN) of the hypothalamus contribute to neurohumoral excitation in heart failure. In the present study, we studied whether NFκB contributes to sympathoexcitation in heart failure by modulating PIC, ROS and renin angiotensin system (RAS) in the PVN.
Methods and results (table⇓): Myocardial infarction (MI) was induced in mice lacking the gene for p50 subunit of NFκB (KO) and age matched wild-type (WT) control mice, and confirmed by echocardiography. At 5 weeks after MI, WT+MI mice exhibited increased left ventricle dilatation and decreased fractional shortening compared to the Sham or KO+MI mice. HPLC revealed significantly higher plasma norepinephrine (NE) levels in WT+MI mice. Real-time RT-PCR in the hypothalamus showed significant increase in the expression of TNF, IL-1β, angiotensin converting enzyme (ACE) and AT-1R in WT+MI mice. Total ROS and superoxide levels measured by electroparamagnetic resonance (EPR) spectroscopy were also significantly increased in the PVN of WT+MI mice. Immunofluorescence studies in the PVN revealed an increased cFOS and decreased nNOS expression in WT+MI mice. However, all these changes were attenuated in Sham and KO+MI mice.
Conclusions: These results indicate that NFκB contribute to neurohumoral excitation by modulating PIC, RAS components and ROS in the PVN of heart failure mice.