Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase- and nuclear factor kappa B-dependent and retinol-independent mechanism.
Serum retinol-binding protein 4 (RBP4) is the sole specific vitamin A (retinol) transporter in blood. Elevation of serum RBP4 in patients has been linked to cardiovascular disease and diabetic retinopathy. However, the significance of RBP4 elevation in the pathogenesis of these vascular diseases is unknown. Here we show that RBP4 induces inflammation in primary human retinal capillary endothelial cells (HRCEC) and human umbilical vein endothelial cells (HUVEC) by stimulating expression of proinflammatory molecules involved in leukocyte recruitment and adherence to endothelium, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). We demonstrate that these novel effects of RBP4 are independent of retinol and the RBP4 membrane receptor STRA6 and occur in part via activation of NADPH oxidase and NF-κB. Importantly, retinol-free RBP4 (apo-RBP4) was as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory molecules in both HRCEC and HUVEC. These studies reveal that RBP4 elevation can directly contribute to endothelial inflammation and therefore may play a causative role in the development or progression of vascular inflammation during cardiovascular disease and microvascular complications of diabetes.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. Krysten-Farjo@ouhsc.edu
Krysten M
KM
Farjo
Rafal A
RA
Farjo
Stacey
S
Halsey
Gennadiy
G
Moiseyev
Jian-Xing
JX
Ma
D001483:Base Sequence; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018076:DNA, Complementary; C573420:ICAM1 protein, human; D018836:Inflammation Mediators; D016328:NF-kappa B; C101326:RBP4 protein, human; D011994:Recombinant Proteins; D054839:Retinol-Binding Proteins, Plasma; D019010:Vascular Cell Adhesion Molecule-1; D014801:Vitamin A; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases