Anti-atherosclerotic mechanism of protocatechuic aldehyde and its relationship with G protein-coupled estrogen receptor-1

Abstract

Protocatechuic aldehyde (PCA), a phenolic aldehyde, has been proposed to have therapeutic potency for treatment of atherosclerosis. Although PCA is known to inhibit the migration and proliferation of vascular smooth muscle cells and intravascular thrombosis, the underlying mechanism remains unclear. In this study, I investigated the protective effect of PCA in endothelial cells and injured vessels in association with G protein-coupled estrogen receptor-1 (GPER-1) in vivo and in vitro.PCA treatment increased cAMP production in Human Umbilical vein endothelial cells (HUVECs) and GPER-1 expression was increased in both HUVECs and a rat aortic explant. PCA and G1, a GPER-1 agonist, reduced H2O2 stimulated ROS production in HUVECs, whereas G15, a GPER-1 antagonist, increased ROS production further. This elevation of ROS production was inhibited by treatment of G15 with PCA or G1. TNFα stimulated the expression of inflammatory markers (VCAM-1, ICAM-1 and CD40), phospho-NF-κB, phospho-p38 and HIF-1α; however, treatment with PCA or G1 down-regulated this expression significantly. Accordingly, increased expression of inflammatory markers by treatment with G15 was inhibited by treatment with PCA.Treatment of rat aorta with PCA or G1 showed accelerated re-endothelization of the endothelium and reduced sprouting and neointima formation. However, aortas from G15-treated rats showed decelerated re-endothelization and increased sprouting and neointima formation. The effects of G15 were restored by treatment with PCA or G1. In addition, in the endothelia of these aortas, PCA and G1 increased CD31 and GPER-1 and decreased VCAM-1 and CD40 expression. In contrast, the opposite effect was observed in G15-treated endothelium. These results suggest that GPER-1 might mediate the protective effect of PCA on the endothelium.