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

Objective—We tested the hypothesis that carvedilol, a &bgr;-adrenoceptor and &agr;-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-&agr; (TNF-&agr;)–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 &mgr;mol/L for 18 hours) or probucol (5 &mgr;mol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-&agr;–stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-&agr;–stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0±2.0% and 55.60±1.0% of control, P<0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0±5.0% of control, P<0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-&agr;–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-&agr;–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.

[1]  Jaw-WenChen,et al.  Ginkgo biloba Extract Inhibits Tumor Necrosis Factor-α–Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells , 2003 .

[2]  Yuh-Lien Chen,et al.  Ginkgo biloba Extract Inhibits Tumor Necrosis Factor-&agr;–Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells , 2003 .

[3]  M. Kitagawa,et al.  Evidence that reactive oxygen species do not mediate NF‐κB activation , 2003 .

[4]  L. Dobrucki,et al.  Third-Generation &bgr;-Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux: A Novel Mechanism for Antihypertensive Action , 2003, Circulation.

[5]  Jaw-Wen Chen,et al.  Differential mononuclear cell activity and endothelial inflammation in coronary artery disease and cardiac syndrome X. , 2003, International journal of cardiology.

[6]  Wei Zhang,et al.  Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells. , 2003, Free radical biology & medicine.

[7]  Qiang Zhang,et al.  Rac1 and Superoxide Are Required for the Expression of Cell Adhesion Molecules Induced by Tumor Necrosis Factor-α in Endothelial Cells , 2003, Journal of Pharmacology and Experimental Therapeutics.

[8]  D. Harrison,et al.  Role of oxidative stress in atherosclerosis. , 2003, The American journal of cardiology.

[9]  M. Kitagawa,et al.  Evidence that reactive oxygen species do not mediate NF-kappaB activation. , 2003, The EMBO journal.

[10]  Shing‐Jong Lin,et al.  Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells. , 2003, Arteriosclerosis, Thrombosis and Vascular Biology.

[11]  K. Kröncke,et al.  Nitric Oxide Inhibits Endothelial IL-1β-induced ICAM-1 Gene Expression at the Transcriptional Level Decreasing Sp1 and AP-1 Activity , 2001, Molecular medicine.

[12]  M. Kaczmarczyk,et al.  Selective inhibition by probucol of vascular cell adhesion molecule-1 (VCAM-1) expression in human vascular endothelial cells. , 2001, Atherosclerosis.

[13]  J. Tardif,et al.  Antioxidants and prevention of restenosis after directional coronary atherectomy. , 2001, Circulation.

[14]  A. Zeiher,et al.  Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol. , 2000, Journal of the American College of Cardiology.

[15]  A. Moreno,et al.  Effects of carvedilol and its analog BM-910228 on mitochondrial function and oxidative stress. , 2000, The Journal of pharmacology and experimental therapeutics.

[16]  D. Sorescu,et al.  Modulation of Protein Kinase Activity and Gene Expression by Reactive Oxygen Species and Their Role in Vascular Physiology and Pathophysiology , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[17]  H. Seo,et al.  Pyrrolidine Dithiocarbamate Inhibits TNF-α-Dependent Activation of NF-κB by Increasing Intracellular Copper Level in Human Aortic Smooth Muscle Cells , 2000 .

[18]  P. Serruys,et al.  Carvedilol for prevention of restenosis after directional coronary atherectomy : final results of the European carvedilol atherectomy restenosis (EUROCARE) trial. , 2000, Circulation.

[19]  J. Mehta,et al.  Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: modulation of Fas/Fas ligand and caspase-3 pathway. , 2000, Cardiovascular research.

[20]  H. Seo,et al.  Pyrrolidine dithiocarbamate inhibits TNF-alpha-dependent activation of NF-kappaB by increasing intracellular copper level in human aortic smooth muscle cells. , 2000, Biochemical and biophysical research communications.

[21]  M. Fried.  Management of hepatitis C in the hemophilia patient. , 1999, The American journal of medicine.

[22]  C. Kunsch,et al.  Oxidative stress as a regulator of gene expression in the vasculature. , 1999, Circulation research.

[23]  J. Loscalzo,et al.  Cellular adhesion molecules and atherogenesis. , 1999, The American journal of medicine.

[24]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[25]  E. Chi,et al.  Inhibition of nuclear factor-kappa B nuclear localization reduces human E-selectin expression and the systemic inflammatory response. , 1998, Circulation.

[26]  A. Malik,et al.  E-selectin expression in human endothelial cells by TNF-α-induced oxidant generation and NF-κB activation. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[27]  A. Aplin,et al.  Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. , 1998, Pharmacological reviews.

[28]  A. Maggioni,et al.  Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study. , 1998, European heart journal.

[29]  M. Yacoub,et al.  Native low density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. , 1998, The Journal of clinical investigation.

[30]  G. Feuerstein,et al.  Carvedilol: preclinical profile and mechanisms of action in preventing the progression of congestive heart failure. , 1998, European heart journal.

[31]  E. Ohlstein,et al.  CARVEDILOL INHIBITS ENDOTHELIN-1 BIOSYNTHESIS IN CULTURED HUMAN CORONARY ARTERY ENDOTHELIAL CELLS , 1998 .

[32]  S. Nattel,et al.  Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. , 1997, The New England journal of medicine.

[33]  C. A. de la Motte,et al.  Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced E-selectin and VCAM-1 expression. , 1997, The American journal of physiology.

[34]  W. Palinski,et al.  Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[35]  O. Aruoma.  Scavenging of hypochlorous acid by carvedilol and ebselen in vitro. , 1997, General pharmacology.

[36]  K Konstantopoulos,et al.  Perspectives Series: Cell Adhesion in Vascular Biology Effects of Fluid Dynamic Forces on Vascular Cell Adhesion , 1996 .

[37]  H. Forman,et al.  Oxidants as stimulators of signal transduction. , 1997, Free radical biology & medicine.

[38]  S. Jay,et al.  Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. , 1997, The New England journal of medicine.

[39]  T. Yue,et al.  Carvedilol prevents low-density lipoprotein (LDL)-enhanced monocyte adhesion to endothelial cells by inhibition of LDL oxidation. , 1995, European journal of pharmacology.

[40]  A. Malik,et al.  H2O2 and Tumor Necrosis Factor-α Activate Intercellular Adhesion Molecule 1 (ICAM-1) Gene Transcription through Distinct cis-Regulatory Elements within the ICAM-1 Promoter (*) , 1995, The Journal of Biological Chemistry.

[41]  R. Ross,et al.  Cell biology of atherosclerosis. , 1995, Annual review of physiology.

[42]  W. Erl,et al.  Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[43]  V. Baichwal,et al.  Three NF-kappa B binding sites in the human E-selectin gene required for maximal tumor necrosis factor alpha-induced expression , 1994, Molecular and cellular biology.

[44]  T. Yue,et al.  Carvedilol, a new vasodilating beta adrenoceptor blocker antihypertensive drug, protects endothelial cells from damage initiated by xanthine-xanthine oxidase and neutrophils. , 1994, Cardiovascular research.

[45]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[46]  T. Yue,et al.  SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, is a potent antioxidant. , 1994, European journal of pharmacology.

[47]  Offermann Mk,et al.  Antioxidants and atherosclerosis: a molecular perspective. , 1994, Heart disease and stroke : a journal for primary care physicians.

[48]  M. Offermann,et al.  Antioxidants and atherosclerosis: a molecular perspective. , 1994, Heart disease and stroke : a journal for primary care physicians.

[49]  T. Yue,et al.  Carvedilol, a new antihypertensive agent, prevents lipid peroxidation and oxidative injury to endothelial cells. , 1993, Hypertension.

[50]  R. Alexander,et al.  Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. , 1993, The Journal of clinical investigation.

[51]  S. Douglas,et al.  Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Hung‐Yuan Cheng,et al.  Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. , 1992, The Journal of pharmacology and experimental therapeutics.

[53]  Gohn Dc,et al.  Polymorphic ventricular tachycardia (Torsade de Pointes) associated with the use of probucol. , 1992 .

[54]  D. Gohn,et al.  Polymorphic ventricular tachycardia (Torsade de Pointes) associated with the use of probucol. , 1992, The New England journal of medicine.

[55]  J. Belch,et al.  Probucol, a superoxide free radical scavenger in vitro. , 1991, Atherosclerosis.

[56]  P. Tarr,et al.  Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription. , 1991, Proceedings of the National Academy of Sciences of the United States of America.