Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and...

Area of Science:

• Cardiovascular Biology
• Immunology
• Aging Research

Background:

• Aging exacerbates atherosclerotic vascular disease risk, with macrophages playing a key role in vascular aging, inflammation, and atherosclerosis.
• NADPH oxidase 4 (NOX4) expression rises with age, linked to mitochondrial dysfunction, inflammation, and atherosclerosis.
• Increased NOX4 is hypothesized to promote aging-associated atherosclerosis via NOX4-dependent mitochondrial oxidative stress, metabolic dysfunction, and macrophage inflammatory phenotype switching.

Purpose of the Study:

• To investigate the role of NOX4 in aging-associated atherosclerosis.
• To determine if NOX4-driven mitochondrial oxidative stress in macrophages contributes to metabolic dysfunction and inflammatory phenotype switching.
• To assess the therapeutic potential of NOX4 inhibition in mitigating aging-related atherosclerosis.

Main Methods:

• Comparative analysis of atherosclerotic lesion morphology and macrophage phenotype in young and aged Apoe^-/- and Nox4^-/-/Apoe^-/- mice fed a Western diet.
• Immunofluorescence, flow cytometry, and mitochondrial respiration assessments were used to analyze macrophage populations and function.
• Pharmacological inhibition of NOX4 using GKT137831 in aged Apoe^-/- mice.

Main Results:

• Aged Nox4^-/- mice exhibited significantly reduced atherosclerotic lesion areas, lower oxidative stress, and a shift towards pro-resolving macrophages compared to aged Apoe^-/- mice.
• Macrophages from aged Apoe^-/- mice displayed impaired mitochondrial function and a glycolytic metabolic switch, whereas Nox4^-/- macrophages maintained aerobic metabolism.
• NOX4 inhibition in aged Apoe^-/- mice attenuated atherosclerosis by reducing macrophage mitochondrial ROS, improving mitochondrial function, and altering macrophage phenotype.

Conclusions:

• Increased NOX4 in aging drives macrophage mitochondrial dysfunction, metabolic reprogramming towards glycolysis, and a pro-inflammatory phenotype, thereby accelerating atherosclerosis.
• Targeting NOX4 or mitochondrial dysfunction presents a promising therapeutic strategy to alleviate vascular inflammation and preserve plaque integrity in aging individuals.
• The study highlights NOX4 as a critical mediator of macrophage dysfunction in vascular aging and atherosclerosis.