Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn119
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Cross talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-
B
1 Shanxi Medical University, Taiyuan 030001, China
2 Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
* Corresponding author: Joseph Francis, B.V.Sc, M.V.Sc, PhD Comparative Biomedical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Phone: +1-225-578-9752 Fax: +1-225-578-9895 jfrancis{at}lsu.edu
* Yu-Ming Kang, MD, PhD Comparative Biomedical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Phone: +1-225-578-9550 Fax: +1-225-578-9895 ymkang{at}lsu.edu
Aims: Nuclear factor – kappa B (NF-
B) is a potent inducer of proinflammatory cytokines (PIC) and oxidative stress in cardiovascular disease. In this study, we determined whether upregulation of NF-B in the hypothalamic paraventricular nucleus (PVN) contributed to neurohumoral excitation either directly, or via interaction with the renin-angiotensin system (RAS), in heart failure (HF).
Methods: Rats were implanted with intracerebroventricular (ICV) cannulae and subjected to coronary artery ligation, or sham surgery (SHAM). Subsequently, animals were ICV treated with the angiotensin type 1 receptor (AT1-R) antagonist losartan (LOS, 20 µg/hr), or SN50 (2µg/hr), which inhibits nuclear translocation of NF-B, or tempol (TEMP, 80 µg/hr), a membrane-permeable superoxide scavenger, or vehicle for 4 weeks.
Results: HF induced a significant increase in the expression of AT1-R, PIC, and NAD(P)H oxidase genes and NF-B p50 in the PVN and in plasma norepinephrine levels when compared with SHAM rats. In contrast, ICV LOS, SN50 or TEMP attenuated PIC, NF-B p50, AT1-R and NAD(P)H oxidase genes in the PVN compared with vehicle-treated HF rats. Treatment with LOS, SN50 or TEMP also reduced plasma levels of norepinephrine, angiotensin II and PIC, and decreased left ventricular end diastolic pressure.
Conclusion: These findings indicate that NF-B mediates the cross talk between RAS and PIC in the PVN in heart failure, and that superoxide stimulates more NF-B in the PVN and contributes to neurohumoral excitation.
KEYWORDS NF-B; heart failure; brain; angiotensin; superoxide
Time for primary review: 30 days
a Both authors contributed equally to this study.
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