Antiatherogenic Effect of Resveratrol Attributed to Decreased Expression of ICAM-1 (Intercellular Adhesion Molecule-1)

Abstract

Objective— Increasing evidence shows that resveratrol has antiatherogenic effects, but its underlying mechanisms are unknown. Thus, we evaluated the molecular mechanisms underlying the antiatherogenic effect of resveratrol. Approach and Results— Using the previously established mouse atherosclerosis model of partial ligation of the left carotid artery, we evaluated the role of resveratrol in antiatherosclerosis. We attempted to determine the mechanisms associated with focal adhesions using vascular endothelial cells. The results showed that resveratrol stimulated focal adhesion kinase cleavage via resveratrol-increased expression of lactoferrin in endothelial cells. Furthermore, we found that an N-terminal focal adhesion kinase fragment cleaved by resveratrol contained the FERM (band 4.1, ezrin, radixin, and moesin)-kinase domain. Furthermore, resveratrol inhibited lipopolysaccharide-stimulated adhesion of THP-1 human monocytes by decreased expression of ICAM-1 (intercellular adhesion molecule-1). A decreased ICAM-1 level was also observed in the left carotid artery of mice treated with resveratrol. To understand the relationship between resveratrol-induced antiinflammation and focal adhesion disruption, endothelial cells were transfected with FERM-kinase. Ectopically expressed FERM-kinase, the resveratrol-cleaved focal adhesion kinase fragment, was found in the nuclear fraction and inhibited the transcription level of icam-1 via the Nrf2 (nuclear factor erythroid 2-related factor 2)-antioxidant response element complex. Finally, ectopically expressed FERM-kinase blocked tumor necrosis factor-α- or IL- (interleukin) stimulated monocytic binding to endothelial cells. Conclusions— Our results show that resveratrol inhibits the expression of ICAM-1 via transcriptional regulation of the FERM-kinase and Nrf2 interaction, thereby blocking monocyte adhesion. These suppressive effects on the inflammatory mechanism suggest that resveratrol delayed the onset of atherosclerosis.

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

“…There is also evidence that butyrate inhibits the acute lung injury in mice by regulating the NFκB signaling pathway [59]. Moreover, Nrf2-HO1 signaling is linked to ICAM-1 expression in a mouse atherosclerosis model [60], in THP-1 macrophages [61], and HaCaT cells [62]. However, in the present study, SnPP blocking HO1 activity could not reverse the inhibition of butyrate in ICAM-1 expression.…”

Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

“…In addition, resveratrol ameliorated atherosclerosis partially through restoring intracellular GSH via AMPK-α activation, resulting in inhibited monocyte differentiation and reduced pro-inflammatory cytokine production [59]. Moreover, resveratrol regulated the band 4.1, ezrin, radixin, and moesin (FERM)-kinase and Nrf2 interaction, leading to decreased expression of ICAM-1 and then the inhibition of monocyte adhesion [63]. Resveratrol also exhibited antithrombotic effects via decreasing the tissue factors like TNF-α, and such action could be facilitated by aortic endothelial cells that could deconjugate resveratrol metabolites to free resveratrol [64].…”

“…In vitro A549 cells 56.25, 112.5 µg/mL Triggering an immune response to protect against non-typeable Haemophilus influenzae without developing resistance [46] In vitro H1HeLa cells, Human nasal epithelia 0-300 µM Inhibiting human rhinoviruses-16 replication and normalized virus-induced IL-6, IL-8, and RANTES as well as the expression of ICAM-1 [47] In vitro Rhabdosarcoma cells 2.5-100 µg/mL Preventing EV71 replication, reducing the virus-induced elevated IL-6 and TNF-α secretion via suppressing IKK/NF-κB signaling pathway [48] In vivo Chickens 200, 400, 800 mg/kg Reducing immunocyte apoptosis in chickens receiving conventional vaccinations, and improving the growth of young chickens [49] In vivo Piglets 3, 10, 30 mg/kg/d Maintaining the immune function and attenuating diarrhea and inflammation [51] In vitro Atlantic salmon macrophages 10, 30, 50 µM Reducing bacterial and inflammatory biomarkers in LPS-challenged primary Atlantic salmon macrophages [52] In Improving central arterial wall stiffening based on its antioxidative and anti-inflammation [7] In vivo Rabbits 2.5 mg/kg Mitigating atrial fibrillation by upregulating PI3K/AKT/eNOS [8] In vitro Peripheral blood mononuclear cells 3-80 µM Blocking atherosclerotic plaque progression by acting against pro-atherogenic oxysterol signaling in M1 and M2 macrophages [57] In vivo Rats 50 mg/kg/day Preventing the activation of inflammasome via downregulating NF-κB p65 and p38 MAPK expression, and upregulating SIRT1 expression [62] In vivo Mice 20 mg/kg Regulated the FERM-kinase and Nrf2 interaction, decreasing the expression of ICAM-1, and inhibiting monocyte adhesion [63] In vivo Rats 1.24 µg/d Improving the cardiac and vascular autonomic function [65] In vitro Human RBCs 100 µM Protecting the erythrocytes via interacting with hemoglobin and reducing heme-iron oxidation [66] Cancers In vitro LNCaP cells 5, 10, 20, 50 µM Inducing the expression of COX-2, promoting ERK1/2 activation, and facilitating p53-dependent anti-proliferation gene expression [14] In vitro; In vivo tBregs; Mice 12.5 µM; 20, 50, 500 µg/mouse Preventing breast cancer metastasis by promoting antitumor immune responses via blunting STAT3, leading to inhibited generation and function of tBregs as well as decreased production of TGF-β [67] In In vitro A2780, OVCAR-3, SKOV-3 cells 10, 50, 100 µM…”

Resveratrol Ameliorates Atherosclerosis Induced by High-fat Diet and LPS in ApoE-/- Mice and Inhibits the Activation of CD4+ T Cells

“…Rather than regulated serum lipids, RES attenuated Trimethylamine-N-Oxide (TMAO)-induced AS in ApoE -/mice [33], ameliorated HFD induced AS in LDLR -/mice [34], countered systemic lupus erythematosus-associated AS [35] and alleviated AS in atherosclerotic mice whose left carotid artery was partial ligated [36]. Our result is consistent with previous studies that RES possess beneficial effects on AS and the influences of RES on AS induced by HFD and LPS was firstly observed in our research.…”