Effects of Protocatechuic Acid on Endothelial Function and HDL Functionality in Hypercholesterolemic Subjects: A Randomized Double-Blind Placebo-Controlled Trial

Background: High-density lipoprotein (HDL) exerts atheroprotective properties, partially by maintaining endothelial function. Protocatechuic acid (PCA) has been shown to improve endothelial function in mice. However, whether PCA improves endothelial function in humans is currently unknown. Our studies aimed to evaluate the effects of PCA on endothelial function and HDL concentration, subclass distribution, and functionality in humans. Methods: A double-blind, randomized, placebo-controlled trial was conducted in 150 hypercholesterolemic participants (aged 35–65 y) daily receiving 20 mg PCA or placebo capsules for 12 weeks. Endothelial function [brachial artery flow-mediated dilation (FMD)], serum cyclic guanosine monophosphate (cGMP), HDL concentration, subclass distribution (pre-β-HDL, HDL3, HDL2), and functionality [endothelial nitric oxide synthase (eNOS) activity] were tested at baseline, 6 weeks, and 12 weeks. Results: PCA consumption for 12 weeks significantly improved brachial artery FMD [1.77% (95% CI: 1.46 to 2.08)] and increased cGMP [11.72 pmol/L (95% CI: 6.16 to 17.28)] as compared to the placebo treatment, along with increased HDL3, decreased HDL2, and non-significantly changed in HDL and pre-β-HDL. PCA consumption also increased eNOS activity of HDL [0.39 (95% CI: 0.29 to 0.49)]. In the PCA group, the changes in HDL functionality on eNOS activity were positively correlated with the changes in brachial artery FMD, cGMP, and HDL3, whereas negatively correlated with HDL2. Conclusions: PCA consumption improves endothelial function and HDL functionality in humans with hypercholesterolemia, with accompanying shifts in HDL subclass distributions. These findings are hypothesis-generating and require confirmation in larger, long-term trials.