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PZ in ischemia-induced neovascularization in vivo. A, Representative pictures of thermal imaging of mice hindlimbs. B, Quantitative summary of pad temperature differences. On POD 21 PZ+/+ mice showed a significant reduction in temperature difference compared to immediately after induction of ischemia and significant lower temperature difference to PZ−/− mice, which offered no changes. Data are given as box plots indicating the median with the 25th and 75th percentiles. ANOVA on ranks repeated measures; * p<0.05 vs. pre OP, § p<0.05 vs. post OP, # p<0.05 vs. other genotype on POD 21, n = 11–16. C, After 21 days, PZ−/− mice treated with AdV-PZ showed significant reduction in temperature difference in the ischemic hindlimb. Data are given as box plots indicating the median with the 25th and 75th percentiles. ANOVA on ranks repeated measures; * p<0.05 vs. pre OP, § p<0.05 vs. post OP; n = 10. D, Representative pictures of M. gastrocnemius muscle tissue after immunofluorescent staining for CD31 (red) or cell nuclei (DAPI, blue). Intracardiac injection of an endothelial specific lectin confirmed functional perfusion of CD31/DAPI double positive capillaries (green). E, PZ+/+ mice exhibited significant higher density of CD31/DAPI-double positive capillaries per square millimeter of ischemic M. gastrocnemius tissue compared to the non-ischemic PZ+/+ muscle tissue. In muscle tissue of PZ−/− mice, ischemia did not result in remarkable neovascularization. The number of CD31/DAPI double-positive cells in ischemic PZ−/− mice M. gastrocnemius was even significantly lower compared to ischemic PZ+/+ mice. Data are given as box plots indicating the median with the 25th and 75th percentiles. ANOVA on ranks; & p<0.05 vs. non-ischemic, # p<0.05 vs. other genotype with ischemia; n = 11–16. F, After exposure of PZ−/− mice to AdV-PZ, the compromised angiogenic phenotype of PZ−/− mice after induction of ischemia was significantly reversed. Data are given as box plots indicating the median with the 25th and 75th percentiles. ANOVA on ranks; & p<0.05 vs. non-ischemic, # p<0.05 vs. AdV-GFP with ischemia, n = 10.
Protein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been elucidated so far. Angiogenic potency of PZ was a...
... Often, an increase in the expression of coagulation factors naturally leads to an increase in the expression of their inhibitors, which includes PZ (Sierko et al. 2012b). While evidence of direct effects of PZ on different cell types is minimal, studies have demonstrated a role for PZ in normal angiogenesis (Butschkau et al. 2014), accumulation of PZ around vascular lesions (Greten et al. 1998) and increased PZ expression surrounding blood vessels in breast cancer tissue (Sierko et al. 2011), all of which indicate a more direct involvement of PZ in endothelial and mural cell biology. Maintaining a balance between pro-and anti-coagulant factors is, therefore, not only critical for blood clot formation and degradation, but also for proper cellular activation and homeostasis within tissues themselves. ...
As a regulator of coagulation, abnormal Protein Z (PZ) expression may lead to the formation of blood clots in humans. While previous studies have shown that PZ protein is altered in several types of cancer, however, additional observations are needed to understand the complex biology involved. Herein, we investigated local alterations in PZ expression in lung adenocarcinomas by measuring gene and protein expression in both cancerous and normal lung tissues. Twenty-two (22) specimens of lung adenocarcinoma and 22 specimens of normal lung tissues from human patients were compared for the expression of PZ. In addition, A549 adenocarcinoma cells were compared to a normal epithelial cell line, 16-HBE, for in vitro PZ expression. In tissues and cells, PZ protein and gene expression were determined using western blot, immunohistochemistry and PCR. Lung adenocarcinoma tissues showed elevated expression of both PZ mRNA and protein compared with healthy tissue. Only protein expression was increased in cultured cell lines, which holds implications for the dominant source of PZ in tissues, as well as protein modifications necessary for PZ function. Protein Z appears to be associated with the presence of lung adenocarcinoma and may be a viable prognostic biomarker for lung cancer.
... Because we did not measure circulating ZPI levels or evaluate variants in the ZPI gene, we are unable to address these questions, but these possibilities will require investigation in future studies. Beyond PZ's interactions with ZPI, it has lately been demonstrated that apart from its associations with thrombosis, PZ also acts on vascular endothelium to promote angiogenesis (32). It remains uncertain, however, whether and how such vascular effects relate to the higher risk of ischemic stroke shown here for elevated PZ concentration. ...
Protein Z (PZ) is a vitamin K-dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischaemic stroke. Although PZ-lowering gene variants have been found to be less common in ischaemic stroke, the relationship remains unclear. We investigated PZ levels and PROZ variants in a multi-ethnic case-control study of unexplained stroke in participants aged 18 to 64. Plasma PZ was measured in cases (≥2 months post-stroke) and controls. PZ polymorphisms G79A (rs3024735) and A13G (2273971) were genotyped. A combined genetic score (0-4 minor alleles) was created assuming additive effects. A total of 715 subjects (1:1.4 cases:controls) were included. Analyses revealed evidence of a non-linear association. After adjusting for demographic and clinical covariates, PZ level >2.5 µg/ml (90(th) %ile) were significantly associated with cryptogenic stroke (OR 2.41 [95 % CI 1.34, 4.34]) as compared with lower levels. Higher genetic score was related to progressively lower levels of PZ, and the presence of four minor alleles was associated with lower odds of stroke (adjusted OR 0.26 [95 % CI 0.07, 0.96]) versus 0 minor alleles. In this multi-ethnic study of young and middle-aged adults, there was evidence of a non-linear positive association between PZ level and unexplained stroke, with a directionally consistent association for genetic variants related to PZ levels and cryptogenic stroke. These findings support elevated PZ levels as a risk factor for cryptogenic stroke.
Background: Human parvovirus B19 (B19V) infection and damage of circulating angiogenic cells (CAC) results in dysfunctional endogenous vascular repair (DEVR) with secondary end-organ damage. Trafficking of CAC is regulated by SDF-1α and the respective receptor CXCR4. We thus tested the hypothesis of a deregulated CXCR4/SDF-1α axis in symptomatic B19V-cardiomyopathy. Methods: CAC were infected in vitro with B19V and transfected with B19V-components. Read-out were: CXCR4-expression and migratory capacity at increasing doses of SDF-1α. In 31 patients with chronic B19V-cardiomyopathy compared to 20 controls read-outs were from blood: migratory capacity, CXCR4 expression on CAC, serum SDF-1α; from cardiac biopsies: SDF-1α mRNA, HIF-1α mRNA, microvascular density, resident cardiac stem cells (CSC), transcardiac gradients of CAC. Results: In vitro B19V-infected CAC showed up-regulation of surface CXCR4 with increased migratory capacity further enhanced by elevated SDF-1α concentrations. Overexpression of the B19V capsid protein VP2 was associated with this effect. Chronic B19V-cardiomyopathy patients showed increased numbers of ischaemia mobilised CAC but DEVR as well as diminished numbers of CAC after transcardiac passage. Cardiac microvascular density and CSC were significantly reduced in B19V-cardiomyopathy. Conclusions: We thus conclude that B19V infection has a direct VP2-mediated negative impact on trafficking of CAC in the presence of impaired cardiac regeneration.
To understand the coagulation changes after off-pump coronary artery bypass (OPCAB) surgery, we evaluated the procoagulant activity of microparticles (MPs) and microparticles exposing tissue factor (MPs-TF), together with the levels of total tissue factor (TF), protein Z (PZ), protein Z-dependent protease inhibitor (ZPI), and factor X (FX) before (first day) and 1 week after surgery (seventh day) in plasma samples from 30 patients. Twenty healthy controls were also included. Compared to the controls, patients scheduled for surgery had significantly higher MPs-TF procoagulant activity and lower TF levels ( P = .0006, P = .02, respectively). In the whole cohort, median procoagulant activity of MPs-TF and median levels of TF and ZPI were significantly lower ( P = .02, P = .0003, and P = .004, respectively), while median levels of PZ and FX were significantly higher ( P = .02 and P = .002, respectively) on the seventh day compared to the first day. Our results suggest that OPCAB surgery has a significant effect on the procoagulant activity of MPs-TF and the PZ system.
Pro-coagulant, anti-coagulant and fibrinolytic pathways are responsible for maintaining haemostatic balance under physiological conditions. Any deviation from these pathways would result in hypercoagulability leading to life threatening diseases like myocardial infarction, stroke, portal vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE). Angiogenesis is the process of sprouting of new blood vessels from pre-existing ones and plays a critical role in vascular repair, diabetic retinopathy, chronic inflammation and cancer progression. Serpins; a superfamily of protease inhibitors, play a key role in regulating both angiogenesis and coagulation. They are characterized by the presence of highly conserved secondary structure comprising of 3 β-sheets and 8–9 α-helices. Inhibitory role of serpins is modulated by binding to cofactors, specially heparin and heparan sulfate proteoglycans (HSPGs) present on cell surfaces and extracellular matrix. Heparin and HSPGs are the mainstay of anti-coagulant therapy and also have therapeutic potential as anti-angiogenic inhibitors. Many of the heparin binding serpins that regulate coagulation cascade are also potent inhibitors of angiogenesis. Understanding the molecular mechanism of the switch between their specific anti-coagulant and anti-angiogenic role during inflammation, stress and regular haemostasis is important. In this review, we have tried to integrate the role of different serpins, their interaction with cofactors and their interplay in regulating coagulation and angiogenesis.