Retinol-Binding Protein 4 Induces Inflammation in Human Endothelial Cells by a NADPH Oxidase- and Nuclear Factor Kappa B-dependent and Retinol-Independent Mechanism
Krysten M. Farjoa,#, Rafal A. Farjob, Stacey Halseya, Gennadiy Moiseyeva and Jian-xing Maa
aDepartment of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
beyecro LLC, Oklahoma City, Oklahoma
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 receruitment 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.