title: Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension.
abstract: OBJECTIVE
  Elevated levels of pro-inflammatory cytokine interleukin-17A (IL-17) are associated with hypertensive autoimmune diseases; however, the connection between IL-17 and hypertension is unknown. We hypothesized that IL-17 increases blood pressure by decreasing endothelial nitric oxide production.
  
  
  RESULTS
  Acute treatment of endothelial cells with IL-17 caused a significant increase in phosphorylation of the inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495). Of the kinases known to phosphorylate eNOS Thr495, only inhibition of Rho-kinase prevented the IL-17-induced increase. IL-17 caused a threefold increase in the Rho-kinase activator RhoA, and this was prevented by an IL-17 neutralizing antibody. In isolated mouse aortas, IL-17 significantly increased eNOS Thr495 phosphorylation, induced RhoA expression, and decreased NO-dependent relaxation responses, all of which were prevented by either an IL-17 neutralizing antibody or inhibition of Rho-kinase. In mice, IL-17 treatment for 1 week significantly increased systolic blood pressure and this was associated with decreased aortic NO-dependent relaxation responses, increased eNOS Thr495 phosphorylation, and increased RhoA expression. Inhibition of Rho-kinase prevented the hypertension caused by IL-17.
  
  
  CONCLUSIONS
  These data demonstrate that IL-17 activates RhoA/Rho-kinase leading to endothelial dysfunction and hypertension. Inhibitors of IL-17 or Rho-kinase may prove useful as anti-hypertensive drugs in IL-17-associated autoimmune diseases.
authors.affiliation: Division of Nephrology & Hypertension, Department of Internal Medicine, Texas A&M Health Science Center College of Medicine/Scott & White Memorial Hospital, 702 SW HK Dodgen Loop, Temple, TX 76504, USA.
authors.forename: Hoanglan
authors.initials: H
authors.lastname: Nguyen
authors.forename: Valorie L
authors.initials: VL
authors.lastname: Chiasson
authors.forename: Piyali
authors.initials: P
authors.lastname: Chatterjee
authors.forename: Shelley E
authors.initials: SE
authors.lastname: Kopriva
authors.forename: Kristina J
authors.initials: KJ
authors.lastname: Young
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006973:Hypertension / Q000209:etiology*; D020381:Interleukin-17 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D000577:Amides; D020381:Interleukin-17; D011725:Pyridines; C108830:Y 27632; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases