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Apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, exhibits anti-atherogenic effects similar to high-density lipoprotein (HDL). However, it remains elusive whether D-4F and HDL share similar molecular mechanisms underlying anti-atherogenic effects and endothelial cell protections. We here compared the metabolic changes in endothelial cells induced by D-4F and HDL against oxidized low-density lipoprotein (ox-LDL), which may be of benefit to understanding the protective mechanisms of HDL and D-4F. Functional assays, including wound healing, transwell migration, and tube formation, were used to evaluate the pro-angiogenic effects of HDL and D-4F. NMR-based metabolomic analysis was employed to explore the protective mechanisms underlying HDL and D-4F. Partial least-squares discriminant analysis (PLS-DA) was performed to assess metabolic profiles, and orthogonal PLS-DA (OPLS-DA) was carried out to identify characteristic metabolites. Moreover, significantly altered metabolic pathways were also analyzed. We found that ox-LDL impaired the migration and tube formation of endothelial cells. Metabolomic analysis showed that ox-LDL triggered oxidative stress, impaired glycolysis, and enhanced glycerophospholipid metabolism. Both HDL and D-4F improved the migration and angiogenesis of endothelial cells, alleviated oxidative stress, and ameliorated disordered glycolysis impaired by ox-LDL. Strikingly, HDL partially attenuated the disturbed glycerophospholipid metabolism, whereas D-4F did not show this effect. In summary, although D-4F shared the similar protective effects with HDL on the migration and angiogenesis of endothelial cells, it could not deduce the molecular mechanisms of HDL completely. Nevertheless, D-4F possesses the potentiality to be exploited as clinically applicable agent for endothelial cell protection and cardiovascular disease treatment.
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