Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways

• Published in: PloS one 2013-09, Vol.8 (9), p.e76679-e76679
• Main Authors: Hwang, Hwan-Jin, Jung, Tae Woo, Hong, Ho Cheol, Choi, Hae Yoon, Seo, Ji-A, Kim, Sin Gon, Kim, Nan Hee, Choi, Kyung Mook, Choi, Dong Seop, Baik, Sei Hyun, Yoo, Hye Jin
• Format: Article
• Language: English
• Subjects: Activation; Adhesion; Adipocytes; AKT protein; Arteriosclerosis; Atherosclerosis; Atherosclerosis - physiopathology; Blotting, Western; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Chemokine CCL2 - metabolism; Chromatin Immunoprecipitation; Cytosol; DNA Primers - genetics; Endocrinology; Endothelial cells; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Growth factors; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Inflammation Mediators - metabolism; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Internal medicine; Kinases; Lipopolysaccharides; Medicine; Metabolic disorders; Metabolic syndrome; Microscopy, Fluorescence; Monocyte chemoattractant protein 1; Monocytes; Neutrophils; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Nuclei (cytology); Obesity; Pathways; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; Rodents; Signal transduction; Signal Transduction - physiology; Signaling; Translocation; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumorigenesis; Umbilical vein; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076679

Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis.