Gene Transfer of Redox Factor-1 Inhibits Neointimal Formation

Abstract

Key Words: apurinic/apyrimidinic endonuclease-1/redox factor-1 Ⅲ vascular smooth muscle cells Ⅲ migration Ⅲ reactive oxygen species Ⅲ spleen tyrosine kinase P latelet-derived growth factor (PDGF) performs crucial functions in the regulation of vascular cell proliferation and migration, resulting in circulatory disorders including atherosclerosis. PDGF stimulates intracellular signal molecules with Src homology 2 (SH2) domains, including Src, phospholipase C, phosphatidylinositol 3-kinase (PI3K), and ras/raf-1. 1,2 Src, PI3K, and phospholipase C␥ perform crucial functions related to actin reorganization, growth, and migration in response to PDGF in the vascular smooth muscle cells, 3 and these activities are mediated by the activation of a family of serine/threonine-specific protein kinases, the mitogen-activated protein kinases (MAPK), most notably p38 MAPK. 4 Recently, we determined that spleen tyrosine kinase (Syk), a 70-kDa non-receptor protein tyrosine kinase harboring 2 SH2 domains, binds to phosphorylated PDGF receptor (PDGF-R) and contributes to PDGF-mediated migration in the vascular smooth muscle. 5 Moreover, PDGF-R transmits its signal into intracellular space with the production of reactive oxygen species (ROS), particularly superoxide (O 2 Ϫ⅐ ) and hydrogen peroxide (H 2 O 2 ). 6,7 PDGF augments O 2 Ϫ⅐ levels through NADPH oxidase (NOX), and the inhibition of NOX activity reduces PDGF-induced chemotaxis in vascular smooth muscle cells. 8,9 Because ROS perform crucial functions in many aspects of cellular function, the redox system can be implicated in the regulation of vascular dysfunction. Furthermore, ROS stimulates PDGF-R phosphorylation. 10 These results indicate that ROS may be involved in the activation of PDGF-R via ROS-activated protein kinases.

Cytoplasmic Localization and Redox Cysteine Residue of APE1/Ref-1 Are Associated with Its Anti-Inflammatory Activity in Cultured Endothelial Cells

“…It is well known that mitogen-activated protein kinase (MAPK)s are activated by growth factors, environmental stresses and inflammatory cytokine (Chen et al, 2001). We previously reported that the overexpression of APE1/Ref-1 using the adenoviral gene transfer system inhibits TNF-α-induced ROS production and VCAM-1 in endothelial cells (Angkeow et al, 2002;Kim et al, 2006;Lee et al, 2009). In addition, p38 MAPK activation by TNF-α was blocked by overexpression of APE1/Ref-1 resulting in inhibition of TNF-α-induced VCAM-1 in endothelial cell .…”

Olibanum Extract Inhibits Vascular Smooth Muscle Cell Migration and Proliferation in Response to Platelet-Derived Growth Factor

“…Many vascular diseases are characterized by the abnormal accumulation of vascular smooth muscle cells in the intima of vessels, a process that is thought to occur, in part, as a result of the migration and proliferation of these cells from the tunica media (Ross, 1999;Lee et al, 2009). Vascular smooth muscle cell migration and proliferation is induced by various inflammatory cytokines and growth factors.…”

Overexpression of Ref-1 Inhibits Lead-induced Endothelial Cell Death via the Upregulation of Catalase

“…However, the inhibition of NADPH oxidase by Ref-1 is another pathway by which intracellular ROS levels might be reduced. It was reported previously that Ref-1 inhibited ROS production via the inhibition of the activity of rac1 GTPase, one subunit of NADPH oxidase Lee et al, 2009). A recent study reported the upregulation of the gp91phox subunit of NADPH oxidase in the brain and renal cortex of lead-exposed animals (Vaziri et al, 2003).…”

“…The enzyme is particularly important under limited glutathione content conditions, such as obtain in lead (Pb)-exposed animals (Hsu, 1981;Hunaiti et al, 1995), and plays a significant role in the development of tolerance to oxidative stress in the adaptive responses of cells (Wassmann et al, 2004 (Grosch et al, 1998;Silber et al, 2002). Conversely, overexpression of Ref-1 repair functions stimulates an increase in resistance to certain alkylating agents and oxidative stresses (Tomicic et al, 1997;Grosch et al, 1998;Kim et al, 2006;Lee et al, 2009). Ref-1 and p53 proteins are required for selenium protection from DNA damage in the human and mouse fibroblasts (Fischer et al, 2006).…”

“…Ref-1 has also been shown to suppress intracellular oxidative stress and apoptosis (Angkeow et al, 2002;Ozaki et al, 2002;Yoo et al, 2004). It was recently reported that vascular endothelial cell activation and vascular inflammation were inhibited by Ref-1 overexpression (Kim et al, 2006;Song et al, 2008;Lee et al, 2009).…”