Ginkgolide B Reduces LOX-1 Expression by Inhibiting Akt Phosphorylation and Increasing Sirt1 Expression in Oxidized LDL-Stimulated Human Umbilical Vein Endothelial Cells

Abstract

Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and ginkgolide B downregulated Nrf2 expression. These results suggest that ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells.

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…5). Consistently, increased SIRT1 and decreased Lox-1 expression levels have also been observed in oxLDL-stimulated human umbilical vein ECs exposed to ginkgolide B, an inhibitor of the platelet-activating factor with anti-inflammatory properties elicited via NF-jB inhibition and reduced ICAM-1 and MCP-1 expression (113). Interestingly, Lox-1 regulation of in vivo thrombus formation depends on the degree of activation by oxLDL.…”

Effect of Allicin against Ischemia/Hypoxia‐Induced H9c2 Myoblast Apoptosis via eNOS/NO Pathway‐Mediated Antioxidant Activity

“…Previous studies reported that allicin protected cells against oxidative stress by inhibiting the generation of intracellular ROS [ 31 , 32 ]. Nrf2 is a redox-sensitive transcription factor that plays a key role in cellular antioxidant defense [ 33 ]. In the presence of oxidative stress, Nrf2 is rapidly degraded by the proteasome system, enters the nucleus, binds to antioxidant response element, and upregulates multiple antioxidant and detoxifying genes, such as HO-1 [ 34 ].…”

Oxidative Stress in Cardiovascular Diseases: Involvement of Nrf2 Antioxidant Redox Signaling in Macrophage Foam Cells Formation

“…The pathogenic role of LOX-1 in atherosclerosis has been extensively elucidated. Silencing of LOX-1 by ginkgolide B in oxLDL stimulated endothelial cells led to inhibition ICAM-1 expression and Akt phosphorylation which results in a reduction of oxidative stress injury in endothelial cells [ 83 ]. In addition, knockdown of LOX-1 in mice fed with high cholesterol diet significantly reduced atherogenesis by sustaining endothelial function and inhibiting pro-inflammatory and pro-oxidants signals.…”