Xing Chen1, My-Ngan Duong2, Stephen J Nicholls3, Christina Bursill4. 1. Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA. 2. Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA; Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia; University of Adelaide, Department of Health and Medical Science, Adelaide, SA, 5000, Australia. Electronic address: myngan.duong@sahmri.com. 3. Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA; Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia; University of Adelaide, Department of Health and Medical Science, Adelaide, SA, 5000, Australia. 4. Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia; University of Adelaide, Department of Health and Medical Science, Adelaide, SA, 5000, Australia.
Abstract
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.
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.