Role of TNF-a in vascular dysfunctions induced by chronic ethanol consumption: involvement of perivascular adipose tissue

Author(s)

Janaina Aparecida Simplicio

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2017-07-31

Examining board members

Carlos Renato Tirapelli; Eliana Hiromi Akamine; Michele Mazzaron de Castro

• Advisor: Carlos Renato Tirapelli; Thiago Mattar Cunha

Abstract

Chronic ethanol consumption is an important risk factor in the development of cardiovascular diseases, inducing increased blood pressure, inflammation, vascular dysfunction and enhanced oxidative stress in several tissues. Furthermore, chronic ethanol consumption induces the production of Tumor necrosis factor-? (TNF-?). Perivascular adipose tissue (PVAT) is known as an important source of adipokines and proinflammatory cytokines. This tissue is involved in the pathophysiology of different cardiovascular diseases. The hypothesis of this work is that the chronic ethanol consumption stimulates the production of TNF-?, which in turn, will induce an increase in reactive oxygen species (ROS) generation, nitric oxide (NO) reduction, vascular inflammation, impairment of PVAT function, alterations of vascular reactivity and increased blood pressure. Therefore, the aim of this study was to investigate the role of TNF-? in chronic ethanol consumption-induced vascular dysfunctions and to evaluate the role of PVAT in such damages. This study demonstrated that chronic ethanol consumption for 12 weeks induced an increase in systolic blood pressure (SBP) in C57BL/6 mice (wild type-WT) and this increase was blunted in TNF-? receptor 1 knockout mice (TNFR1-/-). There was no change in vascular relaxation induced by acetylcholine and sodium nitroprusside (NPS). Ethanol consumption increased the superoxide anion (O2-) generation, thiobarbituric acid reactive species (TBARS) and reduction of hydrogen peroxide (H2O2) levels in aorta without and with PVAT (PVAT- and PVAT+, respectively) from WT animals, but not from TNFR1-/- mice. There was an increase in catalase (CAT) and superoxide dismutase (SOD) activities in aorta PVAT- and PVAT+, decrease on plasma reduced-glutathione (GSH) levels from ethanol-treated WT but not in TNFR1-/-. Ethanol consumption did not change glutathione peroxidase (GPx) activity in any group. Nitrate/nitrite (NOx) aortic levels were decreased in WT animals, but not in TNFR1-/- after chronic ethanol consumption. Ethanol consumption increased TNF-?, IL-6 cytokines and myeloperoxidase activity (MPO) which suggest a strong vascular inflammation and migration of neutrophils into the aortic tissue. Such changes were not observed in TNFR1-/- mice. The results show for the first time the participation of TNF-? in the increase of blood pressure, increase of oxidative stress and vascular dysfunction induced by the chronic ethanol consumption. The perivascular adipose tissue had no beneficial effect on these changes. (AU)

• FAPESP's process: 14/09595-0 - TNF-alpha participation in vascular dysfunction induced by chronic ethanol consumption: involvement of perivascular adipose tissue
• Grantee: Janaina Aparecida Simplicio
• Support Opportunities: Scholarships in Brazil - Doctorate