Binding of activated Factor XII to endothelial cells affects its inactivation by the C1‐esterase inhibitor

Schousboe, Inger

doi:10.1046/j.1432-1033.2003.03367.x

Cited by 29 publications

(22 citation statements)

References 33 publications

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“…Other pathways of bradykinin formation exist, however, contact system activation is the main mediator of attacks of angioedema according to literature [25]. Possibly, FXIIa was formed but we were unable to measure it because C1INH cannot (efficiently) inhibit FXIIa, when it is bound to endothelial cells [26]. Furthermore, enzyme-C1INH complexes are rapidly cleared from the circulation possibly obscuring differences in complex concentrations [27–29].…”

Section: Discussionmentioning

confidence: 99%

Ongoing Contact Activation in Patients with Hereditary Angioedema

et al. 2013

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Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.

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Section: Discussionmentioning

confidence: 99%

Ongoing Contact Activation in Patients with Hereditary Angioedema

et al. 2013

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“…As it has previously been shown that FXIIa binds to the cells in a manner identical to FXII [9], binding of FXIIa was used to quantify relatively the amount of FXII bound to cholesterol‐depleted cells. Normal and cholesterol‐depleted cells in 12‐well microtiter plates were incubated with FXIIa, as described above, and analyzed for the amidolytic activity of cell‐bound FXIIa, as previously described [12]. To each well was added 600 µL of 0.8 m m S‐2302 in 50 m m Tris, 12 m m NaCl, 10 m m EDTA, pH 7.8.…”

Section: Amidolytic Activity Of Cell‐bound Fxiiamentioning

confidence: 99%

Factor XII binding to endothelial cells depends on caveolae

Schousboe¹,

Thomsen²,

Deurs³

2004

European Journal of Biochemistry

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It is now generally accepted that factor XII (FXII) binds to cellular surfaces in the vascular system. One of the suggested receptors of this binding is the glycosylphosphatidylinositol-anchored urokinase-like plasminogen activator (u-PAR) harbored in caveolae/lipid rafts. However, binding of FXII to human umbilical vein endothelial cells (HUVEC) has never been shown to be localized to these specialized membrane structures. Using microscopical techniques, we here report that FXII binds to specific patches of the HUVEC plasma membrane with a high density of caveolae. Further investigations of FXII binding to caveolae were performed by sucrose density-gradient centrifugations. This showed that the majority of FXII, chemically cross-linked to HUVEC, could be identified in the same fractions of the gradient as caveolin-1, a marker of caveolae, while the majority of u-PAR was identified in noncaveolae lipid rafts. Accordingly, cholesterol-depleted cells were found to bind significantly reduced amounts of FXII. These observations, combined with the presence of a minority of u-PAR in caveolae concomitant with FXII binding, indicate that FXII binding to u-PAR may be secondary and depends upon the structural elements within caveolae. Thus, FXII binding to HUVEC depends on intact caveolae on the cellular surface.

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“…Increased levels of cystatin C, a cysteine protease, are observed in obese subjects and associate with CVD [19,20]. Serpin G1, better known as C1 inhibitor, is an inhibitor of kallikrein and factor IIa [21]. Serpin F2 or α-2-antiplasmin, is the primary inhibitor of plasmin in the circulation [22].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle markers in relation to obesity and metabolic complications in patients with manifest cardiovascular disease

Kranendonk

Kleijn

Kalkhoven³

et al. 2014

Cardiovasc Diabetol

109

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BackgroundAlterations in extracellular vesicles (EVs), including exosomes and microparticles, contribute to cardiovascular disease. We hypothesized that obesity could favour enhanced release of EVs from adipose tissue, and thereby contribute to cardiovascular risk via obesity-induced metabolic complications. The objectives of this study were: 1) to investigate the relation between the quantity, distribution and (dys) function of adipose tissue and plasma concentrations of atherothrombotic EV-markers; 2) to determine the relation between these EV-markers and the prevalence of the metabolic syndrome; and 3) to assess the contribution of EV markers to the risk of incident type 2 diabetes.MethodsIn 1012 patients with clinically manifest vascular disease, subcutaneous and visceral fat thickness was measured ultrasonographically. Plasma EVs were isolated and levels of cystatin C, serpin G1, serpin F2 and CD14 were measured, as well as fasting metabolic parameters, hsCRP and adiponectin. The association between adiposity, EV-markers, and metabolic syndrome was tested by multivariable linear and logistic regression analyses. As sex influences body fat distribution, sex-stratified analyses between adipose tissue distribution and EV-markers were performed. The relation between EV-markers and type 2 diabetes was assessed with Cox regression analyses.ResultsHigher levels of hsCRP (β 5.59; 95% CI 3.00–8.18) and lower HDL-cholesterol levels (β-11.26; 95% CI −18.39 – -4.13) were related to increased EV-cystatin C levels, and EV-cystatin C levels were associated with a 57% higher odds of having the metabolic syndrome (OR 1.57; 95% CI 1.19–2.27). HDL-cholesterol levels were positively related to EV-CD14 levels (β 5.04; 95% CI 0.07–10.0), and EV-CD14 levels were associated with a relative risk reduction of 16% for development of type 2 diabetes (HR 0.84, 95% CI 0.75–0.94), during a median follow up of 6.5 years in which 42 patients developed type 2 diabetes.ConclusionsIn patients with clinically manifest vascular disease, EV-cystatin C levels were positively related, and EV-CD14 levels were negatively related to metabolic complications of obesity.

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Binding of activated Factor XII to endothelial cells affects its inactivation by the C1‐esterase inhibitor

Cited by 29 publications

References 33 publications

Ongoing Contact Activation in Patients with Hereditary Angioedema

Ongoing Contact Activation in Patients with Hereditary Angioedema

Factor XII binding to endothelial cells depends on caveolae

Extracellular vesicle markers in relation to obesity and metabolic complications in patients with manifest cardiovascular disease

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