Progranulin Protects Vascular Endothelium against Atherosclerotic Inflammatory Reaction via Akt/eNOS and Nuclear Factor-κB Pathways

Abstract

ObjectiveAtherosclerosis 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.Method and ResultsSignaling 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.ConclusionProgranulin 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.

Inflammatory molecules in Frontotemporal Dementia: Cerebrospinal fluid signature of progranulin mutation carriers

“…# P < 0.05 versus controls. Notably, it is known that progranulin reduces the expression of TNFa and MCP-1 in vascular endothelium (Hwang et al, 2013). Therefore, low TNFa or unchanged MCP-1 CSF levels we observed in GRN patients may be linked to haploinsufficiency.…”

The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms

“…The BCECF/AM-labeled THP-1 cells were incubated with stimulated HUVECs for 30 min, and washed using PBS. The levels of attached THP-1 cells were analyzed using a fluorescence microscope and Spectrofluorometer (PerkinElmer, Bridgeville, PA, USA) at 485 nm/520 nm (Hwang et al, 2013).…”

Growth factor progranulin blocks tumor necrosis factor-α-mediated inhibition of osteoblast differentiation

“…The growth factor PGRN has been shown to inhibit TNF-a directly (Liu, 2011;Tang et al, 2011;Hwang et al, 2013); in this study, we explored the blocking effect of PGRN on the TNF-a-mediated inhibition of osteoblast differentiation. We established a C2C12 osteoblast differentiation cell model via BMP-2 induction, where we confirmed that PGRN effectively blocks the TNF-a-mediated inhibition of alkaline phosphatase activity and bone mineralization.…”

“…A recent study described the protective effect of PGRN on Alzheimer's disease, as well as its positive role in wound healing (He et al, 2003;Pereson et al, 2009). Further studies have reported that PGRN inhibits TNF-a and plays a key role in the pathogenesis of atherosclerosis and rheumatoid arthritis (Liu, 2011;Tang et al, 2011;Hwang et al, 2013). However, the exact effects of PGRN on bone tissue remain to be validated.…”