title: Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension.
abstract: OBJECTIVE
  Understanding the novel signalling pathways involved in the pathogenesis of hypertension is vital for the development of effective therapeutic strategies. Recent evidence suggests a role for Toll-like receptor (TLR) 4 in the development of cardiovascular diseases. Although brain has been implicated in the pathogenesis of hypertension, the role of brain TLR4 in hypertension is largely unexplored. Therefore, we investigated the role of brain TLR4 in angiotensin (Ang) II-induced hypertension and whether central TLR4 blockade has cardioprotective effects in hypertension.
  
  
  RESULTS
  Hypertension was induced in male Sprague-Dawley rats by delivering AngII for 14 days. The rats were administered either specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide, intracerebroventricularly. Blood pressure, and cardiac hypertrophy and function, was evaluated by radiotelemetry and echocardiography, respectively. Blood and paraventricular nucleus were collected for measurement of plasma norepinephrine (NE), tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and TLR4 expression, respectively. Heart was analysed for TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NFκB), and renin-angiotensin system (RAS) components. Hypertensive rats had dramatically increased TLR4 expression compared with normotensive rats. Central blockade of TLR4 delayed progression of hypertension and improved cardiac hypertrophy and function in hypertensive rats. TLR4 blockade significantly reduced myocardial TNF-α, IL-1β, iNOS levels, NFκB activity, and altered RAS components in hypertensive rats. These results were associated with reduced circulating NE levels in VIPER-treated hypertensive rats.
  
  
  CONCLUSIONS
  These results provide mechanistic evidence that AngII-induced hypertensive effects are mediated, at least in part, by brain TLR4, and that brain TLR4 blockade attenuates AngII-induced hypertensive response, possibly via down-regulation of myocardial inflammatory molecules and sympathetic activity.
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
authors.forename: Rahul B
authors.initials: RB
authors.lastname: Dange
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA William Hansel Cancer Prevention Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Deepmala
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA Biomedical Sciences Institute, Sao Paulo University, Sao Paulo, Brazil.
authors.forename: Gustavo S
authors.initials: GS
authors.lastname: Masson
authors.affiliation: Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vila
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Wilson
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Nair
authors.affiliation: Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA jfrancis@lsu.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Francis
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000503:physiopathology*; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019001:Nitric Oxide Synthase
keywords: Angiotensin II; Cytokines; Hypertension; NFκB; TLR4