Obesity, Inflammation, and Exercise Training: Relative Contribution of iNOS and eNOS in the Modulation of Vascular Function in the Mouse Aorta.

Josiane F Silva,Cândido C Coimbra,Steyner F Cortes,Izabella C Correa,Thiago F Diniz,Virginia S Lemos,Paulo M Lima,Roger L Santos

doi:10.3389/fphys.2016.00386

Abstract

Background: The understanding of obsesity-related vascular dysfunction remains controversial mainly because of the diseases associated with vascular injury. Exercise training is known to prevent vascular dysfunction. Using an obesity model without comorbidities, we aimed at investigating the underlying mechanism of vascular dysfunction and how exercise interferes with this process.Methods: High-sugar diet was used to induce obesity in mice. Exercise training was performed 5 days/week. Body weight, energy intake, and adipose tissues were assessed; blood metabolic and hormonal parameters were determined; and serum TNFα was measured. Blood pressure and heart rate were assessed by plethysmography. Changes in aortic isometric tension were recorded on myograph. Western blot was used to analyze protein expression. Nitric oxide (NO) was evaluated using fluorescence microscopy. Antisense oligodeoxynucleotides were used for inducible nitric oxide synthase isoform (iNOS) knockdown.Results: Body weight, fat mass, total cholesterol, low-density lipoprotein cholesterol fraction, insulin, and leptin were higher in the sedentary obese group (SD) than in the sedentary control animals (SS). Exercise training prevented these changes. No difference in glucose tolerance, insulin sensitivity, blood pressure, and heart rate was found. Decreased vascular relaxation and reduced endothelial nitric oxide synthase (eNOS) functioning in the SD group were prevented by exercise. Contractile response to phenylephrine was decreased in the aortas of the wild SD mice, compared with that of the SS group; however, no alteration was noted in the SD iNOS−/− animals. The decreased contractility was endothelium-dependent, and was reverted by iNOS inhibition or iNOS silencing. The aortas from the SD group showed increased basal NO production, serum TNFα, TNF receptor-1, and phospho-IκB. Exercise training attenuated iNOS-dependent reduction in contractile response in high-sugar diet–fed animals, decreased iNOS expression, and increased eNOS expression.Conclusion: Obesity caused endothelium dysfunction, TNFα, and iNOS pathway up-regulation, decreasing vascular contractility in the obese animals. Exercise training was an effective therapy to control iNOS-dependent NO production and to preserve endothelial function in obese individuals.

Highlights

Obesity is an important health problem and is closely associated with the onset and development of cardiovascular and metabolic diseases (Ponce-Garcia et al, 2015)
This study provides evidence that (i) obesity causes TNFα-dependent iNOS up-regulation, which increases basal nitric oxide (NO) production and contributes to impaired aortic function, and (ii) exercise training reduces TNFα/TNF-receptor/NF-κB signaling activation, which differently modulates the imbalance between endothelial nitric oxide synthase (eNOS) and iNOS expression in the aorta under normal and high caloric intake
No significant differences in heart rate, systolic blood pressure, and in serum glucose, triglycerides, and free fatty acids among the groups were observed (Table 1)

Summary

Introduction

Obesity is an important health problem and is closely associated with the onset and development of cardiovascular and metabolic diseases (Ponce-Garcia et al, 2015). The on set and progress of vascular dysfunction are complex and could be related to several alterations, such as insulin resistance (Zecchin et al, 2007), hypertension (Li et al, 2007; Tang and Vanhoutte, 2008) and oxidative stress (Gil-Ortega et al, 2014). Together, these disorders can contribute to a reduction in the production and/or bioavailability of nitric oxide (NO), an important endotheliumdependent relaxant factor, leading to vascular dysfunction (Marchesi et al, 2009; Tziomalos et al, 2010; Davel et al, 2011; Fernández-Alfonso et al, 2013). Using an obesity model without comorbidities, we aimed at investigating the underlying mechanism of vascular dysfunction and how exercise interferes with this process

Methods

Results

Conclusion