cAMP Response Element–Binding Protein Mediates Thrombin-Induced Proliferation of Vascular Smooth Muscle Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 21; no. 11; pp. 1764 - 1769
• Main Authors: Tokunou, Tomotake, Ichiki, Toshihiro, Takeda, Kotaro, Funakoshi, Yuko, Iino, Naoko, Takeshita, Akira
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.2001; Hagerstown, MD Lippincott
• Subjects: Adenoviridae - genetics; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Division; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - physiology; DNA - biosynthesis; Genetic Vectors; Medical sciences; Mitogen-Activated Protein Kinases - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Mutation; Phosphorylation; Phosphoserine - metabolism; Protein Biosynthesis - drug effects; Proto-Oncogene Proteins c-fos - biosynthesis; Proto-Oncogene Proteins c-fos - genetics; Rats; Rats, Sprague-Dawley; RNA, Messenger - biosynthesis; Thrombin - pharmacology; Transcriptional Activation; Cell proliferation; Cell culture; Rat; Enzyme; Pathogenesis; Rodentia; Cyclic AMP; Mitogen-activated protein kinase; Cardiovascular disease; Smooth muscle; Vascular disease; Vertebrata; Mammalia; Epidermal growth factor; Thrombin(drug); Animal; Blood vessel; Atherosclerosis
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/hq2112.098770

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. Although recent reports have suggested that cAMP response element-binding protein (CREB) is necessary for the survival of neuronal cells, the role of CREB in VSMC proliferation is not determined. We examined the role of CREB in thrombin-induced VSMC proliferation and the effect of thrombin on phosphorylation of CREB at Ser133, which is a critical marker for activation by Western blot analysis. Thrombin induced phosphorylation of CREB in a dose-dependent manner. An oligopeptide, SFLLRN, which activates the thrombin receptor, also induced the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase or inhibition of p38 mitogen-activated protein kinase suppressed the thrombin-induced CREB phosphorylation. Inhibition of the epidermal growth factor receptor by AG1478 also inhibited the thrombin-induced CREB phosphorylation. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced c-fos mRNA expression and incorporation of [H]thymidine and [H]leucine. These results suggest that CREB-dependent gene transcription plays a critical role in thrombin-induced proliferation and hypertrophy of VSMCs. Transactivation of the epidermal growth factor receptor and 2 mitogen-activated protein kinase pathways are involved in this process. CREB may be a novel transcription factor mediating the vascular remodeling process induced by thrombin.