Attenuation of Atherosclerosis by Protocatechuic Acid via Inhibition of M1 and Promotion of M2 Macrophage Polarization

Macrophage polarization has a vital impact on the progression of atherosclerosis (AS). Protocatechuic acid (PCA), a flavonol, displays notable atheroprotective effects, but its mechanisms have not been clearly defined. We investigated whether PCA attenuated AS by regulating macrophage polarization. PCA consumption inhibited HCD-induced plaque formation (17.84 and 8.21% in the HCD and HCD with PCA groups, respectively, p < 0.05) and inflammatory responses in apolipoprotein E deficient (ApoE–/–) mice. Moreover, PCA suppressed classically activated macrophage (M1) polarization, which decreased the secretion of nitric oxide synthase (54.63 and 32.86% in the HCD and HCD with PCA groups, respectively, p < 0.05) and proinflammatory factors. PCA promoted alternatively activated macrophage (M2) activation, which increased the expression of arginine I (6.97 and 26.19% in the HCD and HCD with PCA groups, respectively, p < 0.001) and anti-inflammatory factors. PCA also regulated M1–M2 polarization in J774 cells and mouse-bone-marrow-derived macrophages. Finally, PCA reduced PI3K–Akt-mediated nuclear-factor-κB activation, thereby suppressing M1 polarization, and provoked signal-transducers-and-activators-of-transcription-6 phosphorylation and peroxisome-proliferator-activated-receptor-γ activation, leading to enhanced M2 activation. Our data revealed that PCA alleviated AS by regulating M1–M2 conversion.