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Efects of TNF-alpha inhibition on morphofunctional vascular alterations associated with renovascular hypertension

Abstract

The renin angiotensin system activation is implicated on hypertension-induced vascular hypertrophy and endothelial dysfunction. Evidences has suggested that TNF-± cytokine is necessary to angiotensin II-induced cardiac hypertrophy and fibrosis. In addition, TNF-± may to modulate the angiotensin converting enzyme (ACE) activity, but is unknown which TNF-± effects on ACE activity during hypertension in animals or in vitro when ACE is stimulated. Both, angiotensin II and TNF-± may promote the activation of the transcriptional factor NF-kB by mechanisms involving the increased of reactive oxygen species (ROS) formation. In the hypertension, ROS is the main factor responsible to matrix metalloproteinases (MMP) activation. The MMP are endopeptidases implicated in the vascular remodeling. The MMP inhibion have shown decreased hypertension-induced vascular dysfunction and hypertrohy. In addition, the MAP kinases activation, such as c-jun N-terminal quinase (JNK), may occurs in reponse to TNF-± e angiotensin II, and could be implicated in increased MMP expression in endothelial cells. However, is uncertain whether the MMP-2 activation in hypertnsive animals could involve TNF-±/ROS/NF-ºB and/or JNK pathways, and whether these mechanisms could implicated in hypertension-induced vascular morphological and functional alterations. Thus, the hypothesis of the present study is the TNF-± inhibition reverse 2-kidney and 1-clip (2K1C) rats-induced morphological and functional alterations by derease the ACE activity and ROS formation declining transcriptional factor such as, NF-kB and/or MAP kinases such as, JNK resulting in lower MMP-2 activation, which is increased in 2K1C rats. To evaluate this hypothesis, Sham and 2K1C rats will be treated with two different TNF- ± inhibitors (Etanercept and Pentoxyfilline). Pentoxyfilline may be addictional benefits on Etanercept due to its vascular properties such as has shown by some authors. The blood pressure wil be evaluated once a week during all 6 weeks of the treatment. The TNF-± levels will be detected by Elisa kit. The Ace activity will be evaluated by fluorimetric assay in plasma and aorta from animals. Western blotting will be used to detect NF-kB and JNK. The ROS formation will be evaluated by DHE and lucigenin method. The MMP activity and expression will be observed in situ zymography and gelatin zymography thechnique. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MATTOS, B. R.; BONACIO, G. F.; VITORINO, T. R.; GARCIA, V. T.; AMARAL, J. H.; DELLALIBERA-JOVILIANO, R.; FRANCA, S. C.; TANUS-SANTOS, J. E.; RIZZI, E. TNF-alpha inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure. Biochemical Pharmacology, v. 180, OCT 2020. Web of Science Citations: 1.

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