Inverted U‐Shaped Dose‐Response Curve of the Anti‐Atherosclerotic Effect of Protocatechuic Acid in Both Male and Female C57BL/6J Mice

Dietary protocatechuic acid (PCA) inhibits atherosclerosis development in male ApoE−/− mice. However, its anti‐atherosclerotic property in genetically unmodified (wild‐type) male or female mice remains unknown.Five‐week‐old C57BL/6J mice (half males and females) were divided into negative (fed a chow diet), positive (fed an atherogenic diet), or 5, 25, 50, 100, or 200 mg/kg BW/d of PCA (fed an atherogenic diet) groups. Oral gavage with PCA between 25–100 mg/kg BW/d for 25 weeks significantly attenuated atherogenic diet‐induced plaque formation in a dose‐dependent manner, whereas the anti‐atherosclerotic efficiency of 200 mg/kg BW/d of PCA was comparable with that of 50 mg/kg BW/d. PCA did not affect serum lipids (total triglyceride, total cholesterol, HDL cholesterol), pro‐inflammatory cytokines (tumor necrosis factor alpha, IL‐1b, IL‐6), oxidized LDL, and total antioxidant capacity, and acetylcholine or sodium nitroprusside‐induced aortic relaxation. Instead, PCA (≥25 mg/kg BW/d) reduced macrophage accumulation and content of tumor necrosis factor alpha, superoxide, and 4‐hydroxynonenal within plaques, and inhibited monocyte adhesion to aortic endothelium in both male and female mice.PCA inhibits early atherosclerosis formation in both male and female C57BL/6J mice with a “U‐shaped” dose‐response relationship, possibly by reducing inflammation burden and oxidative stress within atherosclerotic plaques.