Myeloperoxidase modification of high-density lipoprotein suppresses human endothelial cell proliferation and migration via inhibition of ERK1/2 and Akt activation

Background and aims: Preclinical studies show high-density lipoproteins (HDL) have a protective and reparative effect on the endothelium. HDL is, however, susceptible to oxidation, which affects function. Myeloperoxidase (MPO)-induced modification of HDL results in loss of anti-apoptotic and anti-inflammatory functions, however, its effect on endothelial proliferation and migration has not been characterized. Methods: HUVECs were co-incubated with MPO-oxidised- or native-HDL (nHDL) in proliferation and migration assays. Signalling proteins were assessed in Western blots. Results: nHDL caused dose-dependent increases of endothelial proliferation and migration. Consistent with an increase in cellular proliferation, HDL also stimulated proliferative cellular nuclear antigen (PCNA) expression and ERK phosphorylation in a concentration-dependent manner, which did not occur with MPO-oxidised HDL. HDL increased Akt phosphorylation, a driver of cellular migration. Contrastingly, MPO-oxidised HDL was unable to increase Akt phosphorylation and extensively-oxidised HDL inhibited Akt phosphorylation. Conclusions: HDL promotes endothelial proliferation and migration, mediated in part via activation of ERK and Akt signalling. MPO-induced oxidative modification of HDL attenuates the endothelial-protective effects of HDL. These findings suggest that in an oxidative milieu, present in ageing and disease, HDL is likely to become ineffective. This has implications for HDL-raising therapies and emphasizes the need for strategies that prevent oxidation-related HDL dysfunction.