Hepatic clearance of tissue‐type plasminogen activator and plasma kallikrein in experimental liver fibrosis

Nagaoka, Márcia Regina; Kouyoumdjian, Maria; Borges, Durval Rosa

doi:10.1111/j.1478-3231.2003.00872.x

Cited by 19 publications

(14 citation statements)

References 24 publications

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“…In parallel to reduced levels of hepatic LRP-1, we observed an increased bioavailability of exogenous, active tPA, with an impairment of tPA clearance by the liver: (1) exogenous tPA 555 remained longer in the blood of alcohol-exposed mice than in control mice and (2) in vivo 2-photon liver microscopy showed an inefficient passage of exogenous tPA 555 into the liver parenchyma after alcohol consumption. Our data add to previous observations in severe hepatic diseases (fibrosis or cirrhosis 38 ), showing that even subtle changes in hepatic function increase tPA plasmatic levels because of reduced clearance.…”

Section: Discussionsupporting

confidence: 86%

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Lemarchand

Gauberti

Lizarrondo

et al. 2015

Stroke

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Background and Purpose-Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke.Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake. Methods-We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques. Results-We found that 6 weeks of alcohol consumption (10% in drinking water) worsens ischemic lesions and cancels the beneficial effects of tPA-induced thrombolysis. We accumulate in vivo and in vitro evidence showing that this aggravation is correlated with a decrease in lipoprotein receptor-related protein 1-mediated hepatic clearance of tPA in alcoholexposed mice. Conclusions-An efficient liver-driven clearance of tPA might influence the safety of thrombolysis after stroke.

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Section: Discussionsupporting

confidence: 86%

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Lemarchand

Gauberti

Lizarrondo

et al. 2015

Stroke

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“…Kallikrein can cleave ITIH4 into 35-and 70-kDa fragments (9 ), which were observed in healthy controls (see Fig. 3A in the online Data Supplement), suggesting that kallikrein is decreased in cirrhosis, a finding that is consistent with previous studies (18 ). a2M cleaves at its thioester site when binding to fibrolytic enzymes (19 ).…”

Section: Discussionsupporting

confidence: 86%

Novel Serum Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients

Gangadharan¹,

et al. 2007

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Background: Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. Methods: We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. Results: We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-␣-trypsin inhibitor heavy chain H4 (ITIH4) fragments, ␣1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-␣2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and ␤2 glycoprotein I (␤2GPI) were increased. In general, ␣2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, ␤2GPI, and thioester-cleaved products of a2M. Conclusions: Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis

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“…Although it is known that P. pastoris has the tendency for hyperglycosylation [37], which could cause changes in the physicochemical properties of the target protein, it seems that glycosylation does not play an important role for rtPA activity as Majidzadeh et al expressed fully active human full-length tPA in E. coli [12]. However, clearance of many circulating glycoproteins is mediated by cell surface receptors for specific terminal monosaccharides of oligosaccharide chains on the protein surface [38]. Hence, glycosylation can affect clearance and half-life of glycoproteins.…”

Section: Pai -1 Concentration (Mg/ml)mentioning

confidence: 99%

Expression of a Novel Chimeric-Truncated tPA in Pichia pastoris with Improved Biochemical Properties

et al. 2014

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Thrombolytic therapy by plasminogen activators (PAs) has been a main goal in the treatment of acute myocardial infarction. Despite improved outcomes of currently available thrombolytic therapies, all these agents have different drawbacks that may result in less than optimal outcomes. In order to make tissue plasminogen activator (tPA) more potent, while being more resistant to plasminogen activator inhibitor-1 (PAI-1) and having a higher affinity to fibrin, a new chimeric-truncated form of tPA (CT tPA) was designed and expressed in Pichia pastoris. This novel variant consists of a finger domain of Desmoteplase, an epidermal growth factor (EGF) domain, a kringle 1 (K1) domain, a kringle 2 (K2) domain, in which the lysine binding site (LBS) was deleted, and a protease domain, where the four amino acids lysine 296, arginine 298, arginine 299, and arginine 304 were substituted by aspartic acid. The chimera CT tPA showed 14-fold increase in its activity in the presence of fibrin compared to the absence of fibrin. Furthermore, CT tPA showed about 10-fold more potency than commercially available full-length tPA (Actylase(®)) and provided 1.2-fold greater affinity to fibrin. A residual activity of only 68 % was observed after incubation of Actylase(®) with PAI-1, however, 91 % activity remained for CT tPA. These promising findings suggest that the novel CT tPA variant might be an acceptable PA with superior characteristics and properties.

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Hepatic clearance of tissue‐type plasminogen activator and plasma kallikrein in experimental liver fibrosis

Abstract: We observed that tPA and RPK clearances were affected differently by fibrosis as well as by different stimuli of the acute-phase response, despite the fact that they share a common hepatic clearance mechanism in normal livers, and they were equally affected in cirrhosis.

Cited by 19 publications

References 24 publications

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Novel Serum Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients

Expression of a Novel Chimeric-Truncated tPA in Pichia pastoris with Improved Biochemical Properties

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