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

Karen Claesen,Dirk Hendriks,Karlijn Hermans,Joachim C Mertens,Lynn Roth,Yani Sim

doi:10.3390/pharmaceutics13101731

Karen Claesen, Dirk Hendriks + Show 4 more

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https://doi.org/10.3390/pharmaceutics13101731

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Journal: Pharmaceutics	Publication Date: Oct 19, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: University of Antwerp

Abstract

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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IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
A Western diet (WD) was continued in both groups for another 15 weeks, but only in one group was the diet supplemented with atorvastatin (10 mg/kg/day, Pfizer, New York, NY, USA)
Our results confirm that atorvastatin downregulates proCPU levels in

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The zymogen procarboxypeptidase U (proCPU, TAFI, proCPB2) circulates in plasma and is converted into the active enzyme carboxypeptidase U (CPU, TAFIa, CPB2) by thrombin(-thrombomodulin) or plasmin [1,2]. CPU potently attenuates fibrinolysis through the cleavage of C-terminal lysines on partially degraded fibrin, thereby interfering with efficient plasminogen activation [2]. Lowering proCPU levels will improve the fibrinolytic capacity and is expected to be beneficial in individuals at high risk for thromboembolic diseases. CPU has been shown to modulate inflammation through cleavage of proinflammatory mediators (e.g., C3a, C5a, bradykinin) [3,4]

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