Effects of Rosuvastatin on the Polarization of Naive Macrophages towards the M1 Phenotype and Production of Inflammatory Cytokines via Nox2 in the Loss of Anti-contractile Effect of Perivascular Adipose Tissue During Obesity

Abstract

The prevalence of obesity has increased worldwide, reaching pandemic levels and Brazil follows the global trend. Obesity, which is defined as a chronic disease that induces damage to different organs and systems and for this reason it figures as a risk factor in the development of cardiovascular complications. The accumulation of fat in different body regions leads to cardiometabolic changes that culminate in cardiovascular damage. Furthermore, obesity affects perivascular adipose tissue (PVAT), which is a complex tissue composed of different cell types, with a predominance of adipocytes. This tissue promotes autocrine, paracrine, or endocrine effects by releasing vasoactive substances that play an important role in of vascular tone. Under pathophysiological conditions, PVAT assumes a pro-oxidative and pro-inflammatory phenotype, characterized by increased recruitment and infiltration of macrophages, production of reactive oxygen species (ROS), and release of pro-inflammatory cytokines and chemokines. Macrophages of the M1 phenotype (pro-inflammatory) participate in oxidative and inflammatory responses, contributing to vascular alterations. The production of ROS by M1 macrophages is directly associated with the increased activity/expression of the catalytic subunit Nox2 of the NADPH oxidase enzyme. Thus, PVAT emerges as a potential therapeutic target for the treatment of vascular dysfunctions induced by obesity. Rosuvastatin has been shown to be effective in the primary and secondary prevention of cardiovascular diseases in different conditions, including heart failure, kidney disease, diabetes, and familial hypercholesterolemia. This statin has pleiotropic effects independent of its inhibitory action in HMG-CoA reductase, including the restoration of endothelial function and anti-inflammatory, antithrombotic, and antioxidant effects. However, the effect of rosuvastatin on PVAT dysfunction (shift to a pro-inflammatory and pro-contractile phenotype) induced by obesity has not been evaluated. The hypothesis of this study is that obesity will increase the recruitment and polarization of M1 macrophages (pro-inflammatory) to PVAT, as well as the activation of Nox2 in these macrophages, a response that will lead to the production of ROS and pro-inflammatory cytokines (IL-6 and TNF-±). Altogether, these effects will contribute to PVAT dysfunction. Rosuvastatin will inhibit the pro-inflammatory and pro-oxidative actions of obesity, thus reversing PVAT dysfunction and restoring its anti-contractile capacity. Therefore, this study aims to fill a gap in the mechanism that leads to inflammation in obesity, with a focus on PVAT, which emerges as an important therapeutic target due to its significance in the vascular system. Furthermore, we propose to evaluate the therapeutic potential of rosuvastatin in reversing vascular damage associated with obesity. For this purpose, Wistar Hannover rats will be fed a high-calorie diet for 13 weeks to induce obesity. The effects of rosuvastatin on the reversal of the loss of the anti-contractile effect of PVAT induced by obesity will be evaluated through statin treatment (10 mg/kg/day; intragastric route) in the last 3 weeks of treatment. Functional (blood pressure, vascular reactivity) and molecular (flow cytometry, ELISA, immunofluorescence...) experiments will be conducted using periaortic PVAT (thoracic region).