Abstract
This study shows that DKK-1, a member of the Dickkopf family and a regulator of the Wnt pathways, represents a novel target of statins which, through the inhibition of HMG-CoA reductase and of non-steroidal isoprenoid intermediates, exert extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. We found that atorvastatin downregulates DKK-1 protein (−88.3 ± 4.1%) and mRNA expression (−90 ± 4.2%) through the inhibition of Cdc42, Rho and Rac geranylgeranylated proteins. Further, a combined approach based on the integration of label-free quantitative mass spectrometry based-proteomics and gene silencing allowed us to demonstrate that DKK-1 itself mediates, at least in part, statin effects on human endothelial cells. Indeed, DKK-1 is responsible for the regulation of the 21% of the statin-modulated proteins, which include, among others, clusterin/apoJ, plasminogen activator inhibitor type 1 (PAI-1), myristoylated alanine-rich C-kinase substrate (MARCKS), and pentraxin 3 (PTX3). The Gene Ontology enrichment annotation revealed that DKK-1 is also a potential mediator of the extracellular matrix organization, platelet activation and response to wounding processes induced by statin. Finally, we found that plasma level of DKK-1 from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) was lower (−42 ± 23%) than that of control animals. Thus, DKK-1 is not only a target of statin but it directly regulates the expression of molecules involved in a plethora of biological functions, thus expanding its role, which has been so far restricted mainly to cancer.
Highlights
DKK-1, a member of the Dickkopf family, was originally identified in Xenopus as an inhibitor of β-catenin-dependent Wnt signalling and an inducer of head formation during embryogenesis, a phenotype that coined the Dickkopf (German for ‘big head, stubborn’) nomenclature[1]
Based on the previous observation that statins decrease DKK-1 in the secretome of the immortalised endothelial hybrid cell line EA.hy. 926, established by fusing a human umbilical vein endothelial cell with a human carcinoma cell line[21,25], we addressed the effect of atorvastatin in the primary human endothelial cells human umbilical vein endothelial cells (HUVECs)
To determine whether the effects of atorvastatin on DKK-1 was caused by inhibition of the mevalonate pathway, we evaluated the ability of mevalonate and its isoprenoid derivatives to counteract the inhibitory effect of atorvastatin on DKK-1
Summary
DKK-1, a member of the Dickkopf family, was originally identified in Xenopus as an inhibitor of β-catenin-dependent Wnt signalling and an inducer of head formation during embryogenesis, a phenotype that coined the Dickkopf (German for ‘big head, stubborn’) nomenclature[1]. Ueland et al.[6] reported increased levels of DKK-1 in experimental and clinical atherosclerosis, both systemically and within the atherosclerotic lesion, with high levels in advanced and unstable disease They showed that platelets and endothelial cells (ECs) are important cellular sources of DKK-1, and provided evidence suggesting that platelet- and endothelial-derived DKK-1 contributes to the inflammatory cross-talk between these cells by inhibiting the canonical β-catenin-dependent Wnt pathway and enhancing NF-kB activation[6]. In line with these findings, plasma DKK-1 levels were found to be significantly higher in patients with type 2 diabetes mellitus (T2DM) compared to healthy subjects, in association with increased levels of endothelial dysfunction and platelet activation markers. We provide evidence that DKK-1 is a target of statin in human primary vascular cells and, by means of a quantitative label-free proteomic approach, we showed that it could mediate several of the pleiotropic effects exerted by this multifaceted class of drugs[24]
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