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.

Protein disulfide isomerase expression increases in resistance arteries during hypertension development. Effects on Nox1 NADPH oxidase signaling

“…Indeed this expression has been shown to be enhanced (Vaziri et al, 1998 ) or reduced (Rodriguez-Rodriguez et al, 2007 ; Xu and Liu, 2013 ). Also, eNOS activation is decreased (Filho et al, 2013 ) and ROS production in aorta of SHR was associated with eNOS uncoupling (Li et al, 2006 ). Taken together, the increase in Nox1 and Nox4 and the reduction of eNOS expression in 12 week old arteries from SHR could be associated with the maintenance of hypertension.…”

Vascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial Cells

“…In these animals, the inhibition of TNF- α prevented increased vascular superoxide production and hypertension mediated by angiotensin II [ 3 ]. Although it has been suggested that several cytokines are involved in vascular damage induced by hypertension, TNF- α inhibition decreases blood pressure and prevents target organ damage in animal studies [ 3 , 6 ]. Also, the inhibition of TNF- α in humans showed BP reduction [ 7 ].…”

“…We recently found that TNF- α inhibition with infliximab reduced systolic BP, left ventricular hypertrophy, and vascular inflammation in spontaneously hypertensive rats (SHR) [ 6 ]. Moreover, hypertensive subjects showed increased arterial stiffness and higher plasma levels of TNF- α compared with normotensive subjects [ 19 ].…”

Participação do TNF-a nas disfunções vasculares induzidas pelo consumo crônico de etanol: envolvimento do tecido adiposo perivascular

“…É bem evidente na literatura a correlação entre esta citocina e aumento da PA. Giachini et al (2009) mostraram que a infusão de TNF-α induz aumento da PA em camundongos WT. Da mesma forma, Filho et al (2013) (Zhang et al, 2009;Giachini et al, 2009;Filho et al, 2013).…”

“…É importante notar que nos animais TNFR1 -/o aumento da PA também foi observado, no entanto essa alteração de PAS foi menor e mais tardia quando comparada aos animais WT, pois aconteceu na quinta semana de tratamento com etanol. Estas observações corroboram dados da literatura evidenciando a participação do TNF-α como um dos mediadores responsáveis pelo aumento e manutenção da PAS (Zhang et al, 2009;Giachini et al, 2009;Filho et al, 2013). No entanto, este é o primeiro trabalho que associa o aumento da PAS mediada pelo TNF-α após o consumo crônico de etanol.…”