title: Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension.
abstract: BACKGROUND
  Despite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. The role of the brain in the initiation and progression of all forms of hypertension is well established, but the role of brain TLR4 in progression of hypertension has never been explored. Therefore, we investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals.
  
  
  METHODS
  Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were administered either a specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide in their PVN for 14 days. MAP was recorded continuously by radiotelemetry. PVN and blood were collected for the measurement of pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β), anti-inflammatory cytokine IL-10, inducible nitric oxide synthase (iNOS), TLR4, nuclear factor (NF) κB activity and plasma norepinephrine (NE) and high mobility group box (HMGB)1 expression, respectively.
  
  
  RESULTS
  Hypertensive rats exhibited significantly higher levels of TLR4 in the PVN. TLR4 inhibition within the PVN attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, iNOS levels, and NFκB activity in SHR but not in WKY rats. These results were associated with a reduction in plasma NE and HMGB1 levels and an increase in IL-10 levels in SHR.
  
  
  CONCLUSIONS
  This study demonstrates that TLR4 upregulation in PVN plays an important role in hypertensive response. Our results provide mechanistic evidence that hypertensive response in SHR are mediated, at least in part, by TLR4 in the PVN and that inhibition of TLR4 within the PVN attenuates blood pressure and improves inflammation, possibly via reduction in sympathetic activity.
authors: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA, 70803, USA. rdange3@tigers.lsu.edu.
authors: Rahul B
authors: RB
authors: Dange
authors: William Hansel Cancer Prevention Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA. dagarw2@tigers.lsu.edu.
authors: Deepmala
authors: D
authors: Agarwal
authors: Department of Biological Sciences, College of Science, Louisiana State University, 202 Life Sciences Building, Baton Rouge, LA, 70803, USA. rteruyama@lsu.edu.
authors: Ryoichi
authors: R
authors: Teruyama
authors: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA, 70803, USA. jfrancis@lsu.edu.
authors: Joseph
authors: J
authors: Francis
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II