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Mild Mitochondrial Uncoupling Decreases Experimental Atherosclerosis, A Proof of Concept
- Source :
- Journal of atherosclerosis and thrombosis. 29(6)
- Publication Year :
- 2021
-
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 diet-induced 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.
- Subjects :
- medicine.medical_specialty
Hypercholesterolemia
030204 cardiovascular system & hematology
Mitochondrion
medicine.disease_cause
2,4-Dinitrophenol
Lesion
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Internal medicine
Internal Medicine
medicine
Macrophage
Glucose homeostasis
Animals
Humans
Mice, Knockout
business.industry
Biochemistry (medical)
Hydrogen Peroxide
Atherosclerosis
Oxidants
Mitochondria
Endocrinology
chemistry
LDL receptor
Knockout mouse
medicine.symptom
Cardiology and Cardiovascular Medicine
business
030217 neurology & neurosurgery
Oxidative stress
Subjects
Details
- ISSN :
- 18803873
- Volume :
- 29
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of atherosclerosis and thrombosis
- Accession number :
- edsair.doi.dedup.....325e9ac07fea3b59ed8be26b46a407ae