Inhibition of Hydrogen Sulfide-induced Angiogenesis and Inflammation in Vascular Endothelial Cells: Potential Mechanisms of Gastric Cancer Prevention by Korean Red Ginseng

Abstract

Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide (H2S) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation. Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities, we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine β-synthase and cystathionine γ-lyase, enzymes that are essential for H2S synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate H2S-induced angiogenesis, implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.

H2S and Blood Vessels: An Overview

“…NaHS was shown to reduce oxLDL-induced foam cell formation in macrophages and TNF-α-stimulated ICAM-1 expression in HUVECs (Zhao et al 2011;Wang et al 2013b). In contrast, Choi et al showed that Korean red ginseng extracts inhibit the expression of inflammatory mediators, including IL-8 and IL-6, via reduced CSE expression and H 2 S production in ECs (Choi et al 2012). Supplement of exogenously applied H 2 S reversed the Korean red ginseng extract-improved inflammation status in ECs.…”

Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide

“…NaHS was shown to reduce oxLDL-induced foam cell formation in macrophages and TNF-α-stimulated ICAM-1 expression in HUVECs Wang et al 2013b). In contrast, Choi et al showed that Korean red ginseng extracts inhibit the expression of inflammatory mediators, including IL-8 and IL-6, via reduced CSE expression and H 2 S production in ECs (Choi et al 2012). Supplement of exogenously applied H 2 S reversed the Korean red ginseng extract-improved inflammation status in ECs.…”

Cell migration and Anti-inflammatory Effect of Red Ginseng Extracts Fermented with Laetiporus Sulphureus

“…사포닌의 화학구조는 크게 당부분(glycone)과 비당부 분(aglycone)으로 구성된 배당체(glucoside)이다. 사포 닌은 항산화 작용이 뛰어나며 면역력을 증강시키고 항염 효과 등이 있는 것으로 알려져 있다 [3][4][5][6]. 이러한 배당체가 체내로 흡수될 때에는 장내 특유 미생물에 의해서 분해되어 흡수되는 것으로 알려져 있다 [7,8].…”