Mild Mitochondrial Uncoupling Decreases Experimental Atherosclerosis, A Proof of Concept

Author(s)

Dorighello, Gabriel G. ; Rovani, Juliana C. ; Paim, Bruno A. ; Rentz, Thiago ; Assis, Leandro H. P. ; Vercesi, Anibal E. ; Oliveira, Helena C. F.

• Document type: Journal article
• Source: JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS; v. 29, n. 6, p. 14-pg., 2022-01-01.

Abstract

Aim: Atherosclerosis is responsible for high morbidity and mortality rates around the world. Local arterial oxidative stress is involved in all phases of atherosclerosis development. Mitochondria is a relevant source of the oxidants, particularly under certain risky conditions, such as hypercholesterolemia. The aim of this study was to test whether lowering the production of mitochondrial oxidants by induction of a mild uncoupling can reduce atherosclerosis in hypercholesterolemic LDL receptor knockout mice. Methods: The mice were chronically treated with very low doses of DNP (2,4-dinitrophenol) and metabolic, inflammatory and redox state markers and atherosclerotic lesion sizes were determined. Results: The DNP treatment did not change the classical atherosclerotic risk markers, such as plasma lipids, glucose homeostasis, and fat mass, as well as systemic inflammatory markers. However, the DNP treatment diminished the production of mitochondrial oxidants, systemic and tissue oxidative damage markers, peritoneal macrophages and aortic rings oxidants generation. Most importantly, development of spontaneous and dietinduced atherosclerosis (lipid and macrophage content) were significantly decreased in the DNP-treated mice. In vitro, DNP treated peritoneal macrophages showed decreased H2O2 production, increased anti-inflammatory cytokines gene expression and secretion, increased phagocytic activity, and decreased LDL-cholesterol uptake. Conclusions: These findings are a proof of concept that activation of mild mitochondrial uncoupling is sufficient to delay the development of atherosclerosis under the conditions of hypercholesterolemia and oxidative stress. These results promote future approaches targeting mitochondria for the prevention or treatment of atherosclerosis. (AU)

• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/02903-9 - Role of CETP expression in the macrophage redox state: possible consequences to inflammation and atherosclerosis
• Grantee: Gabriel de Gabriel Taffarello Dorighello
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/02819-0 - Investigation of glucose and lipid metabolism alterations in a model of nicotinamide nucleotide transhydrogenase mitochondrial (NNT)deficiency .
• Grantee: Juliana Cristine Rovani Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/03402-3 - Study of the association of mitochondrial and endoplasmic reticulum membranes in macrophages in the context of hypercholesterolemia: possible relevance for atherosclerosis
• Grantee: Leandro Henrique de Paula Assis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral