PTEN reduces cuff-induced neointima formation and proinflammatory cytokines

Abstract

reduces cuff-induced neointima formation and proinflammatory cytokines. Am J Physiol Heart Circ Physiol 292: H2824 -H2831, 2007. First published February 2, 2007; doi:10.1152/ajpheart.01221.2006.-An inflammatory response followed by vascular injury plays an important role in neointima formation and development of atherosclerotic lesions, which are in part mediated by proinflammatory cytokines. Using a cuff injury model, we examined the effects of adenovirusmediated overexpression of phosphatase and tensin homology deleted on chromosome 10 (PTEN) on neointima formation and the proinflammatory response. A cuff was placed around the femoral artery, and adenovirus expressing human PTEN type 1 (AdPTEN) or Escherichia coli ␤-galactosidase (AdLacZ) was injected between the cuff and the adventitia. After 14 days, the arteries were examined histopathologically and by Western blotting. The significant reduction of neointima formation by AdPTEN compared with AdLacZ was accompanied by reduced cell proliferation and increased adventitial cell apoptosis. AdPTEN also reduced expression of phosphorylated IB-␣, but not nonphosphorylated IB-␣. Western blotting revealed that AdPTEN reduced the cuff injury-induced expression levels of monocyte chemoattractant protein-1, TNF-␣, and IL-1␤ and their expression in all layers of the arterial wall. In contrast, cuff-induced macrophage invasion, which was also inhibited by AdPTEN, was detected only at the intimal surface and in the adventitia. In cultured vascular smooth muscle cells, PTEN directly inhibited ANG IIinduced monocyte chemoattractant protein-1 expression as quantified by real-time PCR and Western blotting. Our results suggest that overexpression of PTEN reduces neointima formation, possibly in part through inhibition of the inflammatory response by macrophage invasion and proinflammatory cytokine expression. vascular inflammation; monocyte chemoattractant protein-1; gene transfer PHOSPHATASE AND TENSIN homology deleted on chromosome 10 (PTEN) is a multifunctional lipid phosphatase that was originally identified as a tumor suppressor gene (20,22). In addition to its tumor suppression capability, it is also known to modulate several cell functions, including migration, proliferation, and apoptosis (36). These actions of PTEN are mediated by antagonism of the phosphatidylinositol 3-kinase (PI3K)-mediated signaling pathway (22). Moreover, PTEN also has protein tyrosine phosphatase activity, which downmodulates signaling pathways involving focal adhesion kinase (FAK) or Shc (34,36). Modulation of FAK/Shc activity by PTEN affects cell migration and adhesion activated by integrins and other tyrosine kinase receptors (34, 36). PTEN has recently been found to play an essential role in cells of the cardiovascular system (25). PTEN is expressed endogenously and regulates many cell functions in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells (VSMCs), including proliferation, migration, survival/apoptosis, hypertrophy, contractility, metabolism, and mechan...

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

“…[57][58][59][60][61] It was also reported that disruption of PTEN in macrophages significantly increases their phagocytic capability, 22 and that overexpression of PTEN inhibits macrophage invasion and proinflammatory cytokine expression. 62 In our myeloid-specific PTEN KO mice, PTEN expression was also ablated in monocytes, macrophages, and some dendritic cells, which also play critical roles in host defense in bacterial pneumonia. Although the competitive adoptive transfer and in vitro bacteria killing/phagocytosis assays definitively demonstrated that PTEN disruption in neutrophils is at least partially responsible for the enhanced bacteria clearance capability in KO mice, the involvement of other cell types cannot be ruled out.…”

Role of MicroRNA-214–Targeting Phosphatase and Tensin Homolog in Advanced Glycation End Product-Induced Apoptosis Delay in Monocytes

“…In the current study, we demonstrated that AGEs can strongly enhance miR-214 expression in monocytes, which, in turn, impedes monocyte apoptosis via targeting of the proapoptotic molecule PTEN. As an inhibitor of Akt activation, PTEN was demonstrated to be involved in leukocyte inflammatory responses (52,58,59). Downregulation of PTEN would result in increased Akt activity (Fig.…”

A New Role for PTEN in Regulating Transient Receptor Potential Canonical Channel 6-mediated Ca2+ Entry, Endothelial Permeability, and Angiogenesis*

“…The phosphatase domain specifically dephosphorylates the D3 inositol head group of phosphoinositol 3,4,5-triphosphate (PIP 3 ) leading to generation of phosphoinositol 4,5-bisphosphate (PIP 2 ) (1, 2). Thus, through this domain PTEN negatively regulates PI3K-Akt-dependent signaling and thereby controls diverse cellular responses such as neointima formation, neutrophil migration and chemotaxis, angiogenesis, and tumor formation (3)(4)(5)(6)(7)(8)(9). PIP 2 is also the key source for generating cellular diacylglycerol (DAG) and inositol triphosphate, both of which increase intracellular Ca 2ϩ (10).…”