Vascular smooth muscle cells oxidative stress

Oxidized LDL are considered to be one of the major factors associated with the development of atherosclerosis. The earliest event is the transport of LDL into the arterial wall where LDL, being trapped in subendothelial space, are oxidized by oxygen radicals produced by endothelial and arterial smooth muscle cells. The oxidation of LDL in the arterial wall is affected by various factors including hemodynamic forces such as shear stress and stretch force. Thus, it has been shown [177] that stress force imposed on vascular smooth muscle cells incubated with native LDL increased the MDA formation by about 150% concomitantly with the enhancement of superoxide production. It was suggested that oxidation was initiated by NADPH oxidase-produced superoxide and depended on the presence of metal ions. 

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

Li Y, Lappas G, Anand-Srivastava MB. 2007. Role of oxidative stress in angiotensin II-induced enhanced expression of Gi(alpha) proteins and adenylyl cyclase signaling in A10 vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292 H1922-H1930. 

Li, Y., M. Descorbeth, and M.B. Anand-Srivastava. 2008 Role of oxidative stress in high glucose-induced decreased expression of Gia.proteins and adenylyl cyclase signaling in vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 294 H2845-2854. 

Wu, L., and Juurlink, B.H. 2002. Increased methylglyoxal and oxidative stress in hypertensive rat vascular smooth muscle cells. Hypertension 39 809-814. 

The EC-SOD is less responsive to oxidant stress than MnSOD. However, in human fibroblasts, the level of SOD3 is elevated by interferon (IFN)-y and IL-1 [94]. In rat alveolar type II pneumocytes, TNF-a and INF-y elevate SOD3 expression via activation of NF-kB [95]. In vascular smooth muscle cells, expression of EC-SOD is induced by INF-yand IL-4 [96]. Angiotensin II up-reg-ulates EC-SOD synthesis in vascular smooth muscle cells [30]. 

Ruef, J., M. Moser, W. Kubler, and C. Bode. 2001. Induction of endothelin-1 expression by oxidative stress in vascular smooth muscle cells. Cardiovasc. Pathol. 10 311-315. 

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

Cyclophilin A, a member of the immunophilin family, is secreted by vascular smooth muscle cells in response to oxidative stress and mediates extracellular signal-regulated kinase (ERKl/2) activation and vascular smooth muscle cell growth by reactive oxygen species (Jin et al. 2000). Human recombinant cyclophilin A can mimic the effects of secreted cyclophilin A to stimulate ERKl/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERKl/2 activation by cyclophilin A. In vivo, cyclophilin A expression and secretion are increased by oxidative stress and vascular injury. 

Fluid shear influences a number of cellular phenomena, including but not limited to vasoconstriction via vascular smooth muscle cells, mechanoreception via plasma membrane receptors or ion channels, and nitric oxide release via endothelial cells. Two main types of systems dominate the apphcation of fluid shear stress parallel plate and cone-and-plate systems. These systems are most useful for studying cell adhesion and engineering vasculature under physiological flow conditions however, the main challenge of these systems is keeping a homogeneous fluid flow to produce uniform shear stress. 

Studies carried out with complete cells in vivo, cell membranes and other cell fractions point to the selective oxidation of phosphatidylserine (26) to a hydroperoxide (PS-OOH) on oxidative stress caused by toxic agents such as H2O2, t-BuOOH and cumyl hydroperoxide (27). Formation of PS-OOH is observed during apoptosis. These phenomena are important because of the cytotoxic effects of various peroxides used in commercial products coming into direct contact with the human body, as is the case of epidermal keratinocytes in contact with cosmetic formulations" ". The toxic effects of f-BuOOH are associated with vasoconstriction and damage to the vascular smooth muscles ". Global determination methods for primary lipid oxidation products are discussed in Section IV.B. 

Nitric oxide and NOS can be constitutive or inducible. Constitutive nNOS and eNOS occur in neuronal and endothelial cells, respectively, and are activated by CaM. In endothelial cells acetylcholine, bradykinin or blood flow derived shear stress elevate cytosolic Ca2+ with the successive consequences of eNOS activation by CaM, NO production, GC activation by NO, elevation of cGMP, PKG activation, specific protein phosphorylation, vascular smooth muscle relaxation and vascular dilation. 

Jaworski K, Kinard F, Goldstein D, Hol-voet P, Trouet A, et al. 2001. S-nitro-sothiols do not incude oxidative stress, contrary to other nitric oxide donors, in cultures of vascular endothelial or smooth muscle cells. Eur. J. Pharmacol. 425 11-19... 

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