Plasminogen activator-inhibitor , oxidative

Diagrammatic representation of actions of VEGF and receptors. Abbreviations HIF-1, hypoxia-inducible factor LPA, lysophosphatidic acid ox-LDL, oxidized low-density PAl, plasminogen activation inhibitor PIGF, placental growth factor VEGF, vascular endothelial growth factor. 

Fig. 5.4 Angiotensin II mediates multiple physiological and pathophysiological responses in the vessel wall.The vessel wall undergoes numerous structural and functional changes mediated by the. A l l R, all of which are considered proatherogenic once physiological thresholds are crossed. See text for details. Ang II, angiotensin II EC, endothelial cell MC, monocyte/macrophage MMP, matrix metalloprotease NO, nitric oxide PAI-1, plasminogen activator inhibitor-1. ECM, extracellular matrix ROS, reactive oxygen species.

The sensitivity of many serine-protease inhibitors (serpins) to ROIs has been determined in a number of groups and is summarized in Table 2. Of these serine-protease inhibitors, the most sensitive to inactivation by oxidants like OC1- or chloramines are those which contain methionine at or juxtaposed to the reactive centre [49] (e.g. plasminogen activator-inhibitor-1 (PAI-1), oq-proteinase inhibitor and 0(2-antiplasmin). Inactivation is thought to principally be due to the oxidation of these methionine residues to methionine sulfoxide [50-52]. PAI-1, which is rapidly inactivated in plasma, is also extremely sensitive to oxidants like iV-chlorosuccinimide, chloramine-T and H2O2, through a reaction involving oxidation of the reactive-site methionine. 

Since aiAT represents the archetype for the serpin (serine-proteinase inhibitor) superfamily of proteins, it is possible that similar oxidative or proteolytic mechanisms may function in the inactivation of other serpins that are important in controlling the inflammatory cascade. Some serpins contain a readily oxidised reactive-centre methionine residue (e.g. plasminogen activator-inhibitor [108] and a2-antiplasmin [109]), whilst all serpins (including antithrombin III [110] and protease nexin I [111]) contain an exposed loop which is susceptible to cleavage by proteinases. 

Nitric oxide pathway manipulation reflected in CsA chronic nephrotoxicity. Supplementation of the nitric oxide substrate, L-arginine, ameliorated whereas use of the nitric oxide synthase inhibitor, L-NAME, aggravated tubulointerstitial fibrosis [100]. Likewise, CsA-induced upregulation of TGF-(31, plasminogen activator inhibitor 1 and deposihon of extracellular matrix components were aggravated by nitric oxide blockade and ameliorated by nitric oxide enhancement [428]. 

Lim, S., Hung, A.C., and Porter, A.G. (2009). Focused per screen reveals p53 dependence of nitric oxide-induced apoptosis and up-regulation of maspin and plasminogen activator inhibitor-1 in tumor cells. Mol. Cancer Res. 7,55-66. 

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