Carvedilol Inhibits Tumor Necrosis Factor-α–Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells

Abstract

Objective-We tested the hypothesis that carvedilol, a ␤-adrenoceptor and ␣-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-␣ (TNF-␣)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis. Methods and Results-Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 mol/L for 18 hours) or probucol (5 mol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-␣-stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-␣-stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0Ϯ2.0% and 55.60Ϯ1.0% of control, PϽ0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0Ϯ5.0% of control, PϽ0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-␣-stimulated intracellular reactive oxygen species (ROS) production and the activation of redox sensitive nuclear factor kappa B and activator protein-1 transcription pathways. Conclusions-Carvedilol reduced TNF-␣-stimulated endothelial adhesiveness to human MNCs by inhibiting intracellular ROS production, transcription factor activation, and VCAM-1 as well as E-selectin expression, suggesting its potential role in clinical atherosclerosis disease. Key Words: antioxidant Ⅲ atherosclerosis Ⅲ carvedilol Ⅲ cell adhesion molecules Ⅲ endothelium I n the early phase of atherogenesis, cell surface adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and endothelial cell selectin (E-selectin) could express on endothelial cells to recruit circulating mononuclear cells (MNCs), mainly monocytes, and facilitate their binding to endothelium and migrating to subendothelial space. 1-3 Reactive oxygen species (ROS) may serve as a common intracellular messenger for various redox-sensitive transcription pathways that lead to adhesion molecule expression in vascular endothelial cells. 1,4,5 Accumulating in vitro and in vivo evidence showed that substances with antioxidant activity such as probucol and ginkgo biloba extract could scavenge intracellular ROS and inhibit endothelial adhesiveness to monocytes by reducing the expression of various adhesion molecules. 6,7 However, because of the presence of significant side effects or lack of clinical evidence, these drugs are rarely used for human atherosclerosis disease. 8 Carvedilol, 1-[carbazolyl-4-oxy]-3-[(2-methoxyphenoxyethyl)-amino]-propanol-2, a nonselective ␤-adrenoceptor antagonist with ␣1 adrenoceptor blocking and potent antioxidant activity, is currently used for treatment of hypertension or symptomatic heart failure. 9,10 Previous in vitro evidence showed that carvedilol, as an oxidant scavenger, could inhibit cardiomyocyte membrane lipid perox...

Iron Sucrose Accelerates Early Atherogenesis by Increasing Superoxide Production and Upregulating Adhesion Molecules in CKD

“…22,23 Until now, evidence from experimental studies to support the iron hypothesis was fragmentary and contradictory. intravenous iron preparations inhibited proliferation and promoted apoptosis of cultured endothelial cells 24,25 as well as increased MNC-endothelial adhesion in vitro 6,26 ; however, a reliable cell model for atherogenesis [27][28][29] and the exact signaling pathway have not been fully established. Li and Frei 30 have found that iron increased endothelial NOx activity and ROS production in cultured endothelial cells.…”

“…Additionally, ROS is thought to induce endothelial damage through activation of NF-kB, a major redox-sensitive transcription factor that is a key regulator of cytokines, chemokines, and cellular adhesion molecules. 29,31 Moreover, the signal mechanisms of ROS with vascular inflammation have been documented. 32 Previous studies proposed the hypothesis that iron is a pro-oxidant provoking intracellular ROS production, which may induce redox-sensitive transcription pathway activation and adhesion molecule expression, subsequently promoting MNCendothelial adhesion.…”

Chloroform extract of aged black garlic attenuates TNF‐α‐induced ROS generation, VCAM‐1 expression, NF‐κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells

“…Furthermore, it has been also demonstrated that various substances with antioxidant activities, such as PD 098063 (Wolle et al, 1996), probucol (Chen et al, 2003(Chen et al, , 2004, ginkgo biloba extract (Chen et al, 2003) and carvedilol (Chen et al, 2004) inhibit endothelial adhesiveness to monocytes by reducing VCAM-1 expression via suppression of NF-κB signaling pathways.…”

Associations between Endothelin-1 and Adiponectin in Chronic Heart Failure

“…Western blot analyses were performed as described previously [23,24]. Briefly, the 25- to 40-µg protein subjected to 12% SDS-polyacrylamide gel electrophoresis was transferred onto PVDF membranes and then underwent blotting.…”