Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension

• Published in: Cardiovascular research Vol. 97; no. 4; pp. 696 - 704
• Main Authors: Nguyen, Hoanglan, Chiasson, Valorie L, Chatterjee, Piyali, Kopriva, Shelley E, Young, Kristina J, Mitchell, Brett M
• Format: Journal Article
• Language: English
• Published: England 15.03.2013
• Subjects: Amides - pharmacology; Animals; Endothelial Cells - drug effects; Endothelial Cells - physiology; Hypertension - etiology; Interleukin-17 - pharmacology; Male; Mice; Mice, Inbred C57BL; Nitric Oxide - physiology; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; Pyridines - pharmacology; Rats; rho-Associated Kinases - physiology
• ISSN: 1755-3245
• DOI: 10.1093/cvr/cvs422

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. 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. 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.