Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.

Abstract

AIMS:

Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC phenotypic modulation, cytokine production, and enhanced neointima formation.

METHODS AND RESULTS:

Smooth muscle marker expression and induction of pro-inflammatory cytokines were compared in cultured SMC expressing control or PTEN-specific shRNA. Compared with controls, PTEN-deficient SMC exhibited increased phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity, reduced expression of SM markers (SM-alpha-actin and calponin), and increased production of stromal cell-derived factor-1alpha (SDF-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (KC/CXCL1) under basal conditions. PI3K/Akt or mTOR inhibition reversed repression of SM marker expression, whereas PI3K/Akt or NF-kappaB inhibition blocked cytokine induction mediated by PTEN depletion. Carotid ligation in mice with genetic reduction of PTEN specifically in SMC (SMC-specific PTEN heterozygotes) resulted in enhanced neointima formation, increased SMC hyperplasia, reduced SM-alpha-actin and calponin expression, and increased NF-kappaB and cytokine expression compared with wild-types. Lesion formation in SMC-specific heterozygotes was similar to lesion formation in global PTEN heterozygotes, indicating that inactivation of PTEN exclusively in SMC is sufficient to induce considerable increases in neointima formation.

CONCLUSION:

PTEN activation specifically in SMC is a common upstream regulator of multiple downstream events involved in pathological vascular remodelling, including proliferation, de-differentiation, and production of multiple cytokines.

• Authors: Seth B Furgeson, Peter A Simpson, Insun Park, Vicki Vanputten, Henrick Horita, Christopher D Kontos, Raphael A Nemenoff, Mary C M Weiser-Evans
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 86 Issue 2 Pg. 274-82 (May 01 2010) ISSN: 1755-3245 [Electronic] England
• PMID: 20051384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Inflammation Mediators
• Intracellular Signaling Peptides and Proteins
• NF-kappa B
• mTOR protein, mouse
• mTOR protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• Pten protein, mouse
• Pten protein, rat

Topics

• Animals
• Carotid Artery Injuries (enzymology, genetics, immunology, pathology)
• Cell Dedifferentiation
• Cell Proliferation
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Inflammation (enzymology, genetics, immunology, pathology)
• Inflammation Mediators (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Mice, Knockout
• Muscle, Smooth, Vascular (enzymology, immunology, pathology)
• Myocytes, Smooth Muscle (enzymology, immunology, pathology)
• NF-kappa B (metabolism)
• PTEN Phosphohydrolase (deficiency, genetics)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Rats
• Signal Transduction
• TOR Serine-Threonine Kinases
• Tunica Intima (enzymology, immunology, pathology)