Lysophosphatidic Acid Induction of Tissue Factor Expression in Aortic Smooth Muscle Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 2; pp. 224 - 230
• Main Authors: Cui, Mei-Zhen, Zhao, Guojun, Winokur, Allison L, Laag, Essam, Bydash, Jason R, Penn, Marc S, Chisolm, Guy M, Xu, Xuemin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2003; Hagerstown, MD Lippincott
• Subjects: Animals; Aorta - cytology; Aorta - drug effects; Aorta - enzymology; Aorta - metabolism; Biological and medical sciences; Blood vessels and receptors; Cells, Cultured; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Heterotrimeric GTP-Binding Proteins - antagonists & inhibitors; Heterotrimeric GTP-Binding Proteins - physiology; Humans; Lysophospholipids - metabolism; Lysophospholipids - physiology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinase Kinases - physiology; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; p38 Mitogen-Activated Protein Kinases; Pertussis Toxin - pharmacology; Phosphorylation - drug effects; Rats; RNA Stability - drug effects; RNA Stability - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thromboplastin - biosynthesis; Thromboplastin - genetics; Thromboplastin - metabolism; Vertebrates: cardiovascular system; atherosclerosis; Phosphorylation; Extracellular signal-regulated protein kinase; Transcription; Enzyme; Induction; Tissue factor; Mitogen-activated protein kinase; Gene expression; Myocyte; Regulation(control); Gene; Lysophosphatidic acid; Blood vessel; Aorta; Circulatory system; Vascular wall; arterial thrombosis; lipid/lipoprotein metabolism; G protein
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000054660.61191.7D

OBJECTIVE—Tissue factor (TF), the initiator of the coagulation cascade, is expressed by cells in atherosclerotic lesions. Lysophosphatidic acid (LPA) is a component of oxidized lipoproteins and an agent released by activated platelets. The present study investigated whether and how TF expression is regulated by LPA. METHODS AND RESULTS—Northern blotting, Western blotting, and TF activity assays demonstrated that LPA markedly induced TF mRNA, protein, and activity in vascular smooth muscle cells. LPA-induced TF expression is primarily controlled at the transcriptional level. Phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signaling–regulated kinases (ERK1/2) was rapidly and markedly induced by LPA. MEK inhibitors U0126 and PD98059 blocked both ERK activation and the increase in TF mRNA. In contrast, the specific p38 MAP kinase inhibitor SB203580 had no effect on LPA-induced TF mRNA increase. The Gαi protein inhibitor, pertussis toxin, abolished LPA-induced phosphorylation of MEKs and ERKs, as well as the induction of TF mRNA. CONCLUSIONS—Our data demonstrate that a Gαi protein and activation of MEKs and ERKs mediate LPA-induced TF expression. Our data suggest that elevated LPA could be a thrombogenic risk factor by upregulating TF expression. These results may have important implications in vascular remodeling and vascular diseases.