Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats
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Data
2013-01-30
Autores
Gazzoto Filho, Ademir
Kinote, Andrezza
Pereira, Daniel J.
Rennó, André
Santos, Rodrigo C. dos
Ferreira-Melo, Silvia E.
Velloso, Licio A.
Bordin, Silvana
Anhê, Gabriel F.
Moreno Júnior, Heitor
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Resumo
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. © 2012 Elsevier B.V.
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Palavras-chave
eNOS, Hypertension, Infliximab, Insulin resistance, TNFα, caspase 3, endothelial nitric oxide synthase, I kappa B, infliximab, insulin, protein kinase B, stress activated protein kinase, tumor necrosis factor alpha, animal experiment, animal model, animal tissue, antihypertensive activity, antiinflammatory activity, aorta, blood pressure regulation, controlled study, dose response, down regulation, endothelial dysfunction, enzyme activation, enzyme induction, enzyme phosphorylation, heart left ventricle function, heart left ventricle hypertrophy, heart protection, histopathology, insulin like activity, insulin resistance, male, nonhuman, priority journal, protein expression, protein function, rat, signal transduction, spontaneously hypertensive rat, systolic blood pressure, systolic hypertension, Animals, Antibodies, Monoclonal, Aorta, Blood Pressure, Caspase 3, Gene Expression Regulation, Glucose Tolerance Test, Hypertrophy, Left Ventricular, Insulin Resistance, Male, Nitric Oxide Synthase Type III, Phosphorylation, Proto-Oncogene Proteins c-akt, Rats, Rats, Inbred SHR, Rats, Wistar, Signal Transduction, Tumor Necrosis Factor-alpha, Up-Regulation
Como citar
European Journal of Pharmacology, v. 700, n. 1-3, p. 201-209, 2013.