cAMP response element-binding protein mediates thrombin-induced proliferation of vascular smooth muscle cells

Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1764-9. doi: 10.1161/hq2112.098770.

Abstract

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 [(3)H]thymidine and [(3)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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cell Division
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • DNA / biosynthesis
  • Genetic Vectors
  • 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
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Thrombin / pharmacology*
  • Transcriptional Activation

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Phosphoserine
  • DNA
  • Mitogen-Activated Protein Kinases
  • Thrombin