Publications [#196831] of Christopher D. Kontos

Papers Published

1. SB Furgeson, PA Simpson, I Park, V Vanputten, H Horita, CD Kontos, RA Nemenoff, MC Weiser-Evans, Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation., Cardiovascular research, vol. 86 no. 2 (May, 2010), pp. 274-82, ISSN 1755-3245 [doi]
   (last updated on 2011/11/15)

   Abstract:
   OBJECTIVE: 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. 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. CONCLUSIONS: 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.

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