Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-kappaB.
OBJECTIVE
Nuclear factor-kappa B (NF-kappaB) is a potent inducer of pro-inflammatory cytokines (PIC) and oxidative stress in cardiovascular disease. In this study, we determined whether upregulation of NF-kappaB 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).


RESULTS
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 microg/h), or SN50 (2 microg/h), which inhibits nuclear translocation of NF-kappaB, or tempol (TEMP, 80 microg/h), a membrane-permeable superoxide scavenger, or vehicle for 4 weeks. HF induced a significant increase in the expression of AT1-R, PIC, and NAD(P)H oxidase genes and NF-kappaB p50 in the PVN and in plasma norepinephrine (NE) levels when compared with SHAM rats. In contrast, ICV LOS, SN50, or TEMP attenuated PIC, NF-kappaB 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 NE, angiotensin II, and PIC, and decreased left ventricular end diastolic pressure.


CONCLUSIONS
These findings indicate that NF-kappaB mediates the cross-talk between RAS and PIC in the PVN in HF, and that superoxide stimulates more NF-kappaB in the PVN and contributes to neurohumoral excitation.
Kang
Yu-Ming
YM
Shanxi Medical University, Taiyuan 030001, People's Republic of China. ymkang@lsu.edu
Ma
Ying
Y
Elks
Carrie
C
Zheng
Jin-Ping
JP
Yang
Zhi-Ming
ZM
Francis
Joseph
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000008:administration & dosage; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D007263:Infusions, Parenteral; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left
D047228:Angiotensin II Type 1 Receptor Blockers; D003497:Cyclic N-Oxides; D016207:Cytokines; D016166:Free Radical Scavengers; D052002:NF-kappa B p50 Subunit; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; C118258:SN50 peptide; D013113:Spin Labels; D013481:Superoxides; D019255:NADPH Oxidases; D019808:Losartan; C001803:tempol