Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

Claesen, Karen; Mertens, Joachim C.; Leenaerts, Dorien; Hendriks, Dirk

doi:10.3390/ijms22020883

Cited by 20 publications

(12 citation statements)

References 184 publications

(290 reference statements)

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“…Lin and co-workers also suggested that these cells may be a source of proCPU within atherosclerotic plaques as well as in other extra-vascular sites during inflammation [ 21 , 23 ]. Hence, monocyte-derived proCPU could contribute to the increase in plasma proCPU concentration in WD mice, although presumably only to a limited extent since the liver remains the main source of circulation proCPU [ 24 ]. Interestingly, it was demonstrated that inflammatory cytokines (both pro and anti-inflammatory), which are abundantly present and upregulated in atherosclerosis, increase proCPU secretion in monocytes [ 21 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

et al. 2021

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Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−), a model of advanced atherosclerosis, statins do not lower cholesterol. Consequently, studying cholesterol-independent effects of statins can be achieved more straightforwardly in these mice. Female ApoE −/−Fbn1C1039G+/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided into a WD group (receiving WD only) and a WD + atorvastatin group (receiving 10 mg/kg/day atorvastatin +WD) group. After 15 weeks, blood was collected from the retro-orbital plexus, and the mice were sacrificed. Total plasma cholesterol and C-reactive protein (CRP) were measured with commercially available kits. Plasma proCPU levels were determined with an activity-based assay. Total plasma cholesterol levels were not significantly different between both groups, while proCPU levels were significantly lower in the WD + atorvastatin group. Interestingly proCPU levels correlated with CRP and circulating monocytes. In conclusion, our results confirm that atorvastatin downregulates proCPU levels in ApoE−/−Fbn1C1039G+/− mice on a WD, and evidence was provided that this downregulation is a pleiotropic effect of atorvastatin treatment.

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Section: Resultsmentioning

confidence: 99%

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

et al. 2021

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“…Although no physiological TAFI inhibitors have been described, nonspecific carboxypeptidase inhibitors such as the arginine analogs D, L-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and guanidinoethyl-mercaptosuccinic acid have been characterized [13,32,33]. In recent years, several pharmaceutical companies have patented different low molecular weight TAFIa inhibitors, many of which have reached phases I and II of the clinical development phase [34]. However, despite early promising results, several of them were discontinued for various reasons, including but not limited to poor specificity, adverse pharmacokinetic profile, and no benefit over standard treatment [20].…”

Section: Discussionmentioning

confidence: 99%

“…This process was further refined by the development of bispecific antibody fragments which simultaneously target TAFI and plasminogen activator inhibitor-1, called diabodies [35,36], and low molecular weight, low immunogenicity variable antigen-binding domains of camelid antibodies called nanobodies with excellent binding affinity, stability, and solubility [37][38][39]. Several of these newer inhibitors have been listed and summarized in two very insightful review articles published lately [20,34]. This line of research shows much promise in preventing and treating thrombotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Pre-administration of a carboxypeptidase inhibitor enhances tPA-induced thrombolysis in mouse microthrombi: Evidence from intravital imaging analysis

Mathews

Honkura

Sano

et al. 2022

Thrombosis Research

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Introduction: Thrombolysis using recombinant tissue-type plasminogen activator (rt-PA) is the pharmacological treatment of choice in acute thrombotic events. However, a narrow therapeutic window and bleeding complications limit its use. We describe the role of carboxypeptidase inhibitor from potato tuber (PTCI), an inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), on Glu-plasminogen accumulation and microthrombus dynamics in vivo and demonstrate its influence on rt-PA-mediated thrombolysis. Materials and methods: In conjunction with real-time intravital two-photon excitation fluorescence microscopy, we produced and imaged laser-induced microthrombi in the mesenteric venules of Green Fluorescent Protein (GFP)-expressing mice. We examined microthrombus dynamics and thrombolysis patterns in vivo by measuring the changes in the fluorescence intensity of labeled Glu-plasminogen following administration of epsilon aminocaproic acid (EACA), PTCI, and rt-PA. Results: PTCI enhanced Glu-plasminogen accumulation at the core of the thrombus by inhibiting TAFIa, while EACA inhibited this process. Exogenous rt-PA effectively triggered Glu-plasminogen activation within the thrombus and promoted thrombolysis. Administration of PTCI and rt-PA together showed no significant benefit on thrombolysis compared to rt-PA administration alone. However, early-phase systemic administration of PTCI before thrombolytic therapy by rt-PA expedited clot lysis as evidenced by significantly faster time to reach peak Glu-plasminogen fluorescence intensity and shorter time to achieve near-complete clot lysis (P = 0.014 and P = 0.003, respectively). Conclusions: PTCI potentiates rt-PA-mediated thrombolysis when administered early in acute thrombotic events. Further studies are warranted to explore the potential of TAFI inhibitors as adjunct agents in thrombolysis or thromboprophylaxis.

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“…Procarboxypeptidase U (proCPU), also denoted thrombin-activatable fibrinolysis inhibitor (TAFI), is a proenzyme synthesized by the liver that, after activation into CPU (TAFIa) by the key enzymes of coagulation (thrombin) and fibrinolysis (plasmin) is a potent attenuator of fibrinolysis. CPU is unstable at 37 °C (half-life 7-15 min) and is rapidly inactivated into CPUi (TAFIai) [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies confirmed that CPU is activated in ischemic stroke patients treated with intravenous thrombolysis and suggest that it can decrease the efficacy of thrombolytic therapy [12][13][14][15][16]. The development of CPU (TAFIa) inhibitors as profibrinolytic agents in combination with rtPA is, therefore, an attractive concept [10]. However, profibrinolytic therapy may lead to an increased bleeding risk.…”

Section: Introductionmentioning

confidence: 99%

Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients

Mertens

Blanc-Guillemaud

Claesen

et al. 2021

Transl. Stroke Res.

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The antifibrinolytic enzyme carboxypeptidase U (CPU, TAFIa, CPB2) is an appealing target for the treatment of acute ischemic stroke (AIS). Increased insights in CPU activation and inactivation during thrombolysis (rtPA) with or without endovascular thrombectomy (EVT) are required to develop CPU inhibitors as profibrinolytic agents with optimal benefits/ risks. Therefore, CPU kinetics during ischemic stroke treatment were evaluated. AIS patients with documented cerebral artery occlusion receiving rtPA (N = 20) or rtPA + EVT (N = 16) were included. CPU activation during thrombolysis was measured by an ultrasensitive HPLC-based CPU activity method and by an ELISA measuring both CPU and inactivated CPU (CPU + CPUi). Intravenous blood samples were collected at admission and throughout the first 24 h. Additional in situ blood samples were collected in the rtPA + EVT cohort proximal from the thrombus. The NIHSS score was determined at baseline and 24 h. CPU activity and CPU + CPUi levels increased upon rtPA administration and reached peak values at the end of thrombolysis (1 h). High inter-individual variability was observed in both groups. CPU activity decreased rapidly within 3 h, while CPU + CPUi levels were still elevated at 7 h. CPU activity or CPU + CPUi levels were similar in in situ and peripheral samples. No correlation between CPU or CPU + CPUi and NIHSS or thrombus localization was found. The CPU system was rapidly activated and deactivated following thrombolysis and thrombectomy in stroke patients, suggesting that a CPU inhibitor would have to be administered during rtPA infusion and over the next few hours. The high CPU generation variability suggests that some patients may not respond to the treatment. EudraCT number 2017-002760-41.

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Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

Cited by 20 publications

References 184 publications

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

Pre-administration of a carboxypeptidase inhibitor enhances tPA-induced thrombolysis in mouse microthrombi: Evidence from intravital imaging analysis

Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients

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