Anti-tumor necrosis factor-α therapy increases plaque burden in a mouse model of experimental atherosclerosis

Area of Science:

• Cardiovascular Biology
• Immunology
• Pharmacology

Background:

• Atherosclerosis is driven by vascular inflammation, involving oxidized lipids and cytokines like tumor necrosis factor-alpha (TNF-α).
• Genetic studies show TNF-α reduction mitigates atherosclerosis in mouse models.
• The therapeutic potential of pharmacological TNF-α inhibition, using monoclonal antibodies, remains less understood in atherosclerosis.

Purpose of the Study:

• To investigate the impact of pharmacological TNF-α inhibition on atherosclerotic plaque development.
• To evaluate the efficacy of a specific anti-TNF-α monoclonal antibody (CNTO5048) in a mouse model of atherosclerosis.

Main Methods:

• Male Ldlr-/- mice were fed a high-fat, high-cholesterol diet for 6-12 weeks.
• Mice received either the anti-TNF-α antibody CNTO5048 or a control IgG.
• Circulating inflammatory markers, lipid profiles, plaque burden, and gene expression were analyzed.

Main Results:

• CNTO5048 treatment reduced systemic inflammatory markers but did not affect body weight or glucose metabolism.
• Unexpectedly, TNF-α inhibition increased plasma triglycerides and very-low-density lipoprotein (VLDL) cholesterol.
• Plaque burden in the aorta and aortic root increased, with decreased smooth muscle cell content and collagen deposition, alongside elevated inflammatory gene expression in the aortic arch.

Conclusions:

• Pharmacological TNF-α inhibition in Ldlr-/- mice reduces systemic inflammation but exacerbates experimental atherosclerosis.
• Increased plaque burden and reduced stability markers, potentially due to a pro-atherogenic lipid profile, were observed.
• These findings suggest a complex role for TNF-α in atherosclerosis, with potential adverse effects of its pharmacological blockade.