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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 25, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp073
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension

Yu-Ming Kang1,2,3,a,*, Ying Ma3,a, Jin-Ping Zheng3, Carrie Elks2, Srinivas Sriramula2, Zhi-Ming Yang3 and Joseph Francis2,*

1 Shantou University Medical College, Shantou 515041, China
2 Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
3 Shanxi Medical University, Taiyuan 030001, China

* 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, USA, Phone: +1 225 578 9752, Fax: +1 225 578 9895, jfrancis{at}lsu.edu or Yu-Ming Kang, MD, PhD, Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA, Phone: +1 225 578 9550, Fax: +1 225 578 9895, ymkang{at}lsu.edu

Aims: Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether nuclear factor kappa B (NF-{kappa}B) activation in the hypothalamic paraventricular nucleus (PVN) increases oxidative stress and contributes to the ANG II-induced hypertensive response.

Methods: Rats were infused intravenously with ANG II (10 ng/kg per min) or saline for 4 weeks. These rats received either vehicle or losartan (LOS, 20 µg/hr), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 µg/hr), a NF-{kappa}B inhibitor; tempol (TEMP, 80 µg/hr), a superoxide scavenger; LOS (20 µg/hr) and PDTC (5 µg/hr); or TEMP (80 µg/hr) and PDTC (5 µg/hr), given intracerebroventricularly (ICV) via osmotic minipump.

Results: ANG II infusion resulted in increased mean arterial pressure, renal sympathetic nerve activity, plasma pro-inflammatory cytokines (PIC), norepinephrine and aldosterone. These rats also had higher levels of Fra-LI (an indicator of chronic neuronal activation), PIC, phosphorylated IKKβ, NF-{kappa}B subunits, AT1-R, superoxide and gp91phox (a subunit of NAD(P)H oxidase) and lower levels of I{kappa}B{alpha} in the PVN than control animals. ICV treatment with LOS, PDTC or TEMP attenuated these changes, and combined treatment with ICV LOS and PDTC, or ICV TEMP and PDTC prevented these ANG II-induced hypertensive responses.

Conclusion: These findings suggest that an ANG II-induced increase in the brain renin-angiotensin system activates NF-{kappa}B in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-{kappa}B activation and neurohumoral excitation in hypertension.

KEYWORDS Hypertension; nuclear factor-kappa B; brain; angiotensin II; oxidative stress

Time for primary review: 34 days

a Both authors contributed equally to this study.


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