Abstract:In previous studies using a nonhuman primate model of Protein C (PC) activation in vivo, immunoblotting showed substantial amounts of activated PC (APC) in a high molecular weight complex with what was presumed to be a previously unrecognized APC binding protein. This APC complex can also be formed in citrated plasma in vitro. It is of low electrophoretic mobility, sodium dodecyl sulfate (SDS) stable, with an apparent Mr of 320 Kd. Its purification from human plasma was accomplished using barium citrate adsorp… Show more
“…Podocyte injury is the earliest observed morphological feature of FSGS (26,38). A2M is an effective inhibitor of activated protein C (aPC) (39), with recent data indicating aPC as protective against apoptosis of podocytes in DN (40). Thus, inhibition of aPC by A2M may block the protective role of aPC.…”
“…Podocyte injury is the earliest observed morphological feature of FSGS (26,38). A2M is an effective inhibitor of activated protein C (aPC) (39), with recent data indicating aPC as protective against apoptosis of podocytes in DN (40). Thus, inhibition of aPC by A2M may block the protective role of aPC.…”
“…Activated protein C (APC) is inhibited primarily by the serine proteinase inhibitors α 1 âantitrypsin ( α 1AT) [1], protein C inhibitor (PCI) [1], and α 2 âmacroglobulin [2,3]. We recently demonstrated in a large FrenchâCanadian kindred that over half of the variance in the APCâ α 1 AT complex and APCâPCI complex plasma concentrations could be attributed to genetic influences [4].…”
Section: Results Of the Variance Component Linkage Analysis On Plasmamentioning
“…Human A2M is a broad-spectrum proteinase inhibitor, and a cargo protein for growth factors and cytokines in the blood and other extracellular spaces. 21 A2M enhances prothrombotic properties by neutralizing plasmin, plasminogen activators and activated protein C. [22][23][24] and acts as proteinase inhibitor through steric shielding and rapid clearance of the bound proteinases. This binding causes change in A2M conformation to an activated form, which recognizes the low-density lipoprotein receptor-related protein 1 (LRP1).…”
Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24âh after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Î) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19-7.53); SAP:5.46 (1.64-18.74); Îmetalloproteinase 9:1.60 (1.12-2.27)]. The addition of baseline A2M and Îmetalloproteinase 9 or baseline SAP and Îmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: pâ=â0.0205; model-3 with SAP: pâ=â0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Îmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.
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