Lysophosphatidylcholine and Carotid Intima-Media Thickness in Young Smokers: A Role for Oxidized LDL-Induced Expression of PBMC Lipoprotein-Associated Phospholipase A2?

Anna Fratta Pasini,Andrea Pasini,Luciano Cominacini,Ulisse Garbin,Chiara Mozzini,Erika Solani,Mattia Cominacini,Chiara Stranieri,Paola Vallerio,Amar Abderrahmani

doi:10.1371/journal.pone.0083092

Anna Fratta Pasini, Andrea Pasini + Show 8 more

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https://doi.org/10.1371/journal.pone.0083092

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Journal: PloS one	Publication Date: Dec 17, 2013
Citations: 46	License type: CC BY 4.0

Affiliation: University of Verona

Abstract

BackgroundAlthough cigarette smoking has been associated with carotid intima-media thickness (CIMT) the mechanisms are yet not completely known. Lysophosphatidylcholine (lysoPC), a main product of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, appears to be a major determinant of the pro-atherogenic properties of oxidized LDL (oxLDL) and to induce proteoglycan synthesis, a main player in intimal thickening. In this study we assessed whether cigarette smoking-induced oxidative stress may influence plasma Lp-PLA2 and lysoPC and Lp-PLA2 expression in peripheral blood mononuclear cells (PBMC), as well as the relationship between lysoPC and CIMT.Methods/Results45 healthy smokers and 45 age and sex-matched subjects participated in this study. Smokers, compared to non-smokers, showed increased plasma concentrations of oxLDL, Lp-PLA2 and lysoPC together with up-regulation of Lp-PLA2 (mRNA and protein) expression in PBMC (P<0.001). Plasma Lp-PLA2 positively correlated with both lysoPC (r=0.639, P<0.001) and PBMC mRNA Lp-PLA2 (r=0.484, P<0.001) in all subjects. Moreover CIMT that was higher in smokers (P<0.001), positively correlated with lysoPC (r=0.55, P<0.001). Then in in vitro study we demonstrated that both oxLDL (at concentrations similar to those found in smoker’s serum) and oxidized phospholipids contained in oxLDL, were able to up-regulate mRNA Lp-PLA2 in PBMC. This effect was likely due, at least in part, to the enrichment in oxidized phospholipids found in PBMC after exposure to oxLDL. Our results also showed that in human aortic smooth muscle cells lysoPC, at concentrations similar to those found in smokers, increased the expression of biglycan and versican, two main proteoglycans.ConclusionsIn smokers a further effect of raised oxidative stress is the up-regulation of Lp-PLA2 expression in PBMC with subsequent increase of plasma Lp-PLA2 and lysoPC. Moreover the correlation between lysoPC and CIMT together with the finding that lysoPC up-regulates proteoglycan synthesis suggests that lysoPC may be a link between smoking and intimal thickening.

Highlights

Cigarette smoking is a major risk factor for atherosclerotic vascular disease and it is an important factor contributing to premature vascular aging [1,2,3]
Since in vitro studies have suggested that oxidized LDL (oxLDL) increase lipoproteinassociated phospholipase A2 (Lp-PLA2) expression and that lysoPC may have a role in intimal expansion [24], this study aimed to assess whether cigarette smoking-induced oxidative stress affects Lp-PLA2 expression in peripheral blood mononuclear cells (PBMC) and Lp-PLA2 and lysoPC plasma concentrations, as well as the relationship between lysoPC and carotid intima-media thickness (CIMT) in otherwise healthy smokers
A-B, our results demonstrated a significantly increased expression of Lp-PLA2 in smokers compared to non-smokers. These findings together with the fact that in all subjects we found a positive correlation between the expression of mRNA Lp-PLA2 in PBMC and the plasma concentrations of Lp-PLA2 (r=0.484, P

Summary

Introduction

Cigarette smoking is a major risk factor for atherosclerotic vascular disease and it is an important factor contributing to premature vascular aging [1,2,3]. In vitro observations have demonstrated that lysoPC is a major determinant of the proatherogenic properties of oxLDL and activates the redoxsensitive inflammatory pathways by increasing the recruitment of leukocytes and by inducing endothelial dysfunction and apoptosis of endothelial and vascular smooth muscle cells (SMCs) [8,11]. In this study we assessed whether cigarette smoking-induced oxidative stress may influence plasma Lp-PLA2 and lysoPC and LpPLA2 expression in peripheral blood mononuclear cells (PBMC), as well as the relationship between lysoPC and CIMT. In in vitro study we demonstrated that both oxLDL (at concentrations similar to those found in smoker’s serum) and oxidized phospholipids contained in oxLDL, were able to up-regulate mRNA Lp-PLA2 in PBMC. Conclusions: In smokers a further effect of raised oxidative stress is the up-regulation of Lp-PLA2 expression in PBMC with subsequent increase of plasma Lp-PLA2 and lysoPC. The correlation between lysoPC and CIMT together with the finding that lysoPC up-regulates proteoglycan synthesis suggests that lysoPC may be a link between smoking and intimal thickening

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