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FFAR4 Deficiency Increases Necrotic Cores in Advanced Lesions of ApoE-/- Mice-Brief Report
Gage M Stuttgen1,2,3, Jordan M Bobek1,2, Renee Penoske2,4
1Department of Biochemistry (G.M.S., J.M.B., M.L., S.N.H., D.S.), Medical College of Wisconsin, Milwaukee.
Background:
FFAR4 (free fatty acid receptor 4) has emerged as a target for preventing cardiovascular disease through its ability to control macrophage inflammation and foam cell formation. Previous studies have shown that FFAR4 activation can protect against the accumulation of arterial plaque buildup in atherosclerotic animal models. The goal of our study is to test the hypothesis that FFAR4 deficiency will increase atherosclerotic plaque development in apoE-/- mice.
Methods:
Male and female apoE-/-/Ffar4-/- mice and their apoE-/- controls were fed a Western diet for 8 or 16 weeks to assess early and advanced atherosclerotic lesions, respectively. At the end of each study, atherosclerotic plaque severity was determined by analyzing the aortic sinus lesion area of the heart and the en face lesion area of the aortic arch.
Results:
Following 8 weeks of Western diet feeding, lesions from apoE-/-/Ffar4-/- male and female mice had 33% and 22% decreases, respectively, in the aortic sinus lesion area with no changes in the aortic arch lesion area. After 16 weeks of Western diet feeding, the lesions showed no changes in the area or volume of the aortic sinus between apoE-/-/Ffar4-/- mice and apoE-/- controls. However, male apoE-/-/Ffar4-/- mice had a 27% increase in the plaque lesion area in the aortic arch compared with apoE-/- controls. Despite similar sizes of lesions in the aortic sinus, apoE-/-/Ffar4-/- mice had larger necrotic cores compared with the apoE-/- control mice. In fact, male and female mice had 43% and 37% increases in the necrotic lesion area, respectively.
Conclusions:
These data suggest a novel role for FFAR4 in reducing necrotic core lesion formation and support a protective role for FFAR4 in stabilizing atherosclerotic plaques.
Insights
Mice lacking free fatty acid receptor 4 (FFAR4) showed reduced early plaque but increased advanced plaque and necrotic cores. FFAR4 deficiency appears to worsen atherosclerosis, particularly in later stages.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Disease Research
Background:
- Free fatty acid receptor 4 (FFAR4) is a potential target for cardiovascular disease prevention.
- FFAR4 activation is known to protect against arterial plaque buildup.
- FFAR4 influences macrophage inflammation and foam cell formation.
Purpose of the Study:
- To investigate the role of FFAR4 deficiency in the development of atherosclerosis.
- To test the hypothesis that FFAR4 deficiency exacerbates atherosclerotic plaque development in apolipoprotein E-deficient (apoE-/-) mice.
Main Methods:
- Male and female apoE-/-/Ffar4-/- mice and apoE-/- controls were fed a Western diet for 8 or 16 weeks.
- Atherosclerotic lesion severity was assessed by measuring aortic sinus and aortic arch lesion areas.
- Necrotic core areas were quantified in advanced lesions.
Main Results:
- After 8 weeks, apoE-/-/Ffar4-/- mice showed reduced aortic sinus lesions.
- After 16 weeks, male apoE-/-/Ffar4-/- mice exhibited increased aortic arch plaque area.
- FFAR4 deficiency led to significantly larger necrotic cores in both male and female mice.
Conclusions:
- FFAR4 plays a protective role in stabilizing atherosclerotic plaques.
- FFAR4 deficiency promotes the development of necrotic cores, indicating plaque instability.
- These findings highlight FFAR4 as a novel therapeutic target for mitigating advanced atherosclerosis.
