Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction.
Circulating levels of free fatty acids are commonly elevated in patients with the metabolic syndrome and exert, through activating proinflammatory pathways, harmful effects of the vascular endothelium. In this study, we examined the effect of palmitate (PA) on endothelial C-reactive protein (CRP) expression and the role of CRP in PA-induced nitric oxide (NO) inhibition. Palmitate increased, in a dose-dependent manner, CRP protein expression and production in human aortic endothelial cells (HAECs). Induction of CRP protein was mimicked by ceramide, whereas bromopalmitate and other common free fatty acids such as oleate or linoleate were ineffective. Palmitate also elicited reactive oxygen species production in HAECs, an effect prevented by protein kinase C (PKC) inhibition and adenosine monophosphate-activated kinase (AMPK) activation. Palmitate-treated HAECs showed increased CRP messenger RNA expression and nuclear factor (NF)-κB activation. Induction of CRP expression by PA was prevented by antioxidants and normalized by PKC and mitogen-activated protein kinase inhibitors. Disrupting NF-κB and Janus kinase/signal transducers and activators of transcription pathways or inducing AMPK activation also suppressed the stimulatory effect of PA on CRP messenger RNA expression. Finally, in HAECs, PA reduced NO release, an effect reversed by anti-CRP antibody. These data demonstrate that PA-induced endothelial CRP expression involves PKC-driven oxidative stress, possibly through AMPK inhibition, and activation of downstream redox-sensitive signaling pathways, including NF-κB. They further support a role for endothelial cell-derived CRP as mediator of the suppressive effect of PA on NO production.
Mugabo
Yves
Y
Centre Hospitalier de l'Université de Montréal Research Centre, Notre-Dame Hospital, Department of Medicine, Montreal, Quebec, Canada.
Mukaneza
Yvette
Y
Renier
Geneviève
G
D001011:Aorta / Q000378:metabolism*; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D002518:Ceramides; D005227:Fatty Acids; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D009569:Nitric Oxide; D002097:C-Reactive Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases