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G protein-coupled estrogen receptor-1 is involved in the protective effect of protocatechuic aldehyde against endothelial dysfunction.

ABSTRACT: Protocatechuic aldehyde (PCA), a phenolic aldehyde, has therapeutic potency against 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, we investigated the protective effect of PCA on endothelial cells and injured vessels in vivo in association with G protein-coupled estrogen receptor-1 (GPER-1). With PCA treatment, cAMP production was increased in HUVECs, while 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. These elevations were inhibited by co-treatment with PCA or G1. TNF? stimulated the expression of inflammatory markers (VCAM-1, ICAM-1 and CD40), phospho-NF-?B, phospho-p38 and HIF-1?; however, co-treatment with PCA or G1 down-regulated this expression significantly. Likewise, increased expression of inflammatory markers by treatment with G15 was inhibited by co-treatment with PCA. In re-endothelization, aortic ring sprouting and neointima formation assay, rat aortas treated 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 co-treatment with PCA or G1. Also, 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.

SUBMITTER: Kong BS

PROVIDER: S-EPMC4239058 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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G protein-coupled estrogen receptor-1 is involved in the protective effect of protocatechuic aldehyde against endothelial dysfunction.

Kong Byung Soo BS Cho Yoon Hee YH Lee Eun Jig EJ

PloS one 20141120 11

Protocatechuic aldehyde (PCA), a phenolic aldehyde, has therapeutic potency against 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, we investigated the protective effect of PCA on endothelial cells and injured vessels in vivo in association with G protein-coupled estrogen receptor-1 (GPER-1). With PCA treatment, cAMP production was increased in ...[more]

PMID: 25411835

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Project description:Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.

Dataset Information

G protein-coupled estrogen receptor-1 is involved in the protective effect of protocatechuic aldehyde against endothelial dysfunction.

Publications

G protein-coupled estrogen receptor-1 is involved in the protective effect of protocatechuic aldehyde against endothelial dysfunction.

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