Participation of potassium channels and mitochondrial dynamics of macrophages in the pathophysiology of Atherosclerosis

• Grant number: 20/08238-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2021
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Lincon Felipe Lima Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases, AP.JP
• Associated scholarship(s): 23/05669-8 - Participation of mitoKATP in the activation of the NLRP3 inflammasome, BE.EP.DR

Abstract

The Obesity epidemic already affects more than 650 million people worldwide and predisposes to the development of several comorbidities, such as Atherosclerosis and Type 2 Diabetes. During Obesity, macrophages infiltrate adipose tissue that assume a pro-inflammatory and contribute to low-grade local and systemic inflammation and subsequent insulin resistance. Blood hypercholesterolemia leads to the accumulation of lipids in macrophages, which acquire a phenotype called foam cells that adhere to the vessels, initiating an Atherosclerosis. Studies with previous atherosclerotic mice models that the activation of the nuclear LXR receptor in ApoE active macrophages inducing reverse cholesterol transport, which results in the attenuation of Atherosclerosis. Macrophages have a malleable metabolism and can change their profile from pro-inflammatory to anti-inflammatory under the named conditions. Initial studies demonstrated an essential role of the Kv1.3 potassium channel in modulating the transit of cholesterol to the macrophage cytoplasm, preventing its differentiation into foam cells. These results indicate a still unknown relationship between K channels and LXR and ApoE. At the center of cell metabolism are mitochondria that have dynamic characteristics, fusion and biogenesis or fission and mitophagy provide the nutritional and bioelectric stimuli they serve, contributing to the phenomenon that the macrophage will carry. Potassium channels are primarily responsible for variations in the electrical potential of the membrane, which affects oxidative phosphorylation, the nutrition sensor modules AMPK and mTORC1 and affects the membrane transporters, leading macrophages to assume a pro-inflammatory or anti-inflammatory . These facts make potassium channels a common link between mitochondrial dynamics and cell cholesterol transport. Obesity is a model that inflammation, hypercholesterolemia and hyperglycemia induces Atherosclerosis, so to understand what happens with macrophages in this situation, a study that integrates all these factors is necessary. This project aims to fill this gap, jointly studying the effect of potassium channels on mitochondrial dynamics and macrophage metabolism over atheromatous plaques, developing conditions of hyperglycemia and hypercholesterolemia. The results of the study will bring further clarification on the mechanics responsible for the polarization of macrophages, which may open the future field for pharmaceutical interventions in the prevention of Obesity-associated Atherosclerosis. (AU)