ABC | Volume 110, Nº6, June 2018

Original Article Endothelial Dysfunction and Inflammation Precedes Elevations in Blood Pressure Induced by a High-Fat Diet Jorge Camargo Oishi, 1 Cynthia Aparecida Castro, 1 Karina Ana Silva, 1 Victor Fabricio, 1 Evelin Capelari Cárnio, 2 Shane A. Phillips, 3 Ana Claudia Garcia de Oliveira Duarte, 1 Gerson Jhonatan Rodrigues 1 Universidade Federal de São Carlos (UFSCar), 1 São Paulo, SP - Brazil Universidade de São Paulo (USP), Ribeirão Preto, 2 SP - Brazil University of Chicago Medical Center, 3 Chicago, Illinois - USA Mailing Address: Jorge Camargo Oishi • Rua Rosalino Belline, 455. Postal Code 13564-050, Santa Paula, São Carlos, SP – Brazil E-mail: jorgeoishi@hotmail.com Manuscript received July 18, 2017, revised manuscript September 14, 2017, accepted October 06, 2017 DOI: 10.5935/abc.20180086 Abstract Background: Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension. Objective: To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model. Methods: We fed male Wistar rats (eight-week age) with a standard diet (Control - CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin -6, tumor necrosis factor- α , C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05. Results: Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP. Conclusion: Our results show the time-course of deleterious effects and their correlation with obesity. (Arq Bras Cardiol. 2018; 110(6):558-567) Keywords: Hypertension; Endothelium / abnormalities; Diet, High-Faties; Nitric Oxide; Dyslipidemias. Introduction Currently, obesity and associated comorbidities are one of the major health problems in developed and developing countries, reducing both the quality and quantity of life and increasing the risk of mortality. 1 Obesity is characterized by excessive fat tissue storage and is strongly associated with the development of cardiovascular diseases, dyslipidemia and hypertension. There is an associated pro-inflammatory environment that appears to worsen cardiovascular outcomes 2,3 and according to the World Health Organization, 4 cardiovascular diseases are currently one of the major causes of mortality in the world. A great number of metabolic disorders are caused by obesity; among them endothelial dysfunction plays an important role in the development of insulin resistance and hypertension. 5 Almost thirty-five years ago, it was discovered that endothelial cells could modulate relaxations and contractions of the underlying vascular smooth muscle, which allowed for the concept that vascular tonus control is endothelium-dependent of the underlying vascular smooth muscle. 6-8 The endo t he l i um p r oduce s s eve r a l “r e l ax i ng factors” (EDRFs, endothelium-derived relaxing factors), hyperpolarizing factors (EDHFs), as well as contractile factors (EDCFs). Through a fine balance between the release of EDRFs and EDCFs, the endothelium plays a vital role in maintaining circulatory homeostasis. Any change in this balance may result in endothelial dysfunction. 5,8 Previous studies have demonstrated the onset of hypertension and endothelial dysfunction in obesity induced by a high-fat diet. 9,10 However, whether and in which order they appear has not been well defined and the temporal relationships between weight gain, endothelial dysfunction and blood pressure following a high-fat diet have not been determined. Therefore, the aim of the present study was to determine the time course of inflammation, endothelial dysfunction and the increase in blood pressure following a high-fat diet designed to induce obesity. 558