Blockade of the Ras-extracellular signal-regulated kinase 1/2 pathway is involved in smooth muscle 22 alpha-mediated suppression of vascular smooth muscle cell proliferation and neointima hyperplasia.

Abstract

OBJECTIVE:

Vascular smooth muscle cells (VSMCs) can switch between differentiated and dedifferentiated phenotypes, and this phenotype switch is believed to be essential for repair of vascular injury. We studied the inhibitory effect of smooth muscle 22 alpha (SM22 alpha) on VSMC proliferation in vitro and in vivo and explored the potential molecular mechanisms of this effect.

METHODS AND RESULTS:

By using coimmunoprecipitation and glutathione S-transferase pull-down assays, we have shown that SM22 alpha binds to Ras in SM22 alpha-overexpressed VSMCs in the presence or absence of platelet-derived growth factor-BB stimulation. SM22 alpha arrested cell cycle progression through segregation of Ras with Raf-1 and downregulation of the Raf-1-MEK1/2-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling cascade. The inhibitory effect of SM22 alpha on VSMC proliferation was verified in vivo. The infection of rat carotid arteries with recombinant adenovirus encoding SM22 alpha inhibited neointimal hyperplasia via suppression of the Raf-1-MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway.

CONCLUSIONS:

These findings suggest that high expression of SM22 alpha inhibits cell proliferation via reduction of the response to mitogen stimuli in VSMCs and provide a novel mechanism by which VSMCs maintain their contractile phenotype and resist mitogenic stimuli in an SM22 alpha-dependent manner.

• Authors: Li-Hua Dong, Jin-Kun Wen, George Liu, Michael A McNutt, Sui-Bing Miao, Rui Gao, Bin Zheng, Hailin Zhang, Mei Han
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 4 Pg. 683-91 (Apr 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20139360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Microfilament Proteins
• Muscle Proteins
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• transgelin
• Becaplermin
• Proto-Oncogene Proteins c-raf
• Raf1 protein, rat
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• ras Proteins

Topics

• Adenoviridae (genetics)
• Animals
• Becaplermin
• Carotid Artery Injuries (enzymology, etiology, pathology, physiopathology)
• Catheterization (adverse effects)
• Cell Cycle
• Cell Dedifferentiation
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Down-Regulation
• Genetic Vectors
• Humans
• Hyperplasia
• Immunoprecipitation (methods)
• MAP Kinase Kinase 1 (metabolism)
• MAP Kinase Kinase 2 (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Male
• Microfilament Proteins (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Muscle Proteins (genetics, metabolism)
• Muscle, Smooth, Vascular (enzymology, injuries, pathology, physiopathology)
• Myocytes, Smooth Muscle (enzymology, pathology)
• Phenotype
• Platelet-Derived Growth Factor (metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-raf
• Proto-Oncogene Proteins c-sis
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Time Factors
• Transfection
• Vasoconstriction
• ras Proteins (metabolism)