title: Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats.
abstract: High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Ademir Gazzoto
authors.initials: AG
authors.lastname: Filho
authors.forename: Andrezza
authors.initials: A
authors.lastname: Kinote
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pereira
authors.forename: André
authors.initials: A
authors.lastname: Rennó
authors.forename: Rodrigo C
authors.initials: RC
authors.lastname: dos Santos
authors.forename: Silvia E
authors.initials: SE
authors.lastname: Ferreira-Melo
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhê
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno Junior
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D017379:Hypertrophy, Left Ventricular / Q000150:complications; D000069285:Infliximab; D007333:Insulin Resistance; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3