Adiporedoxin suppresses endothelial activation via inhibiting MAPK and NF-κB signaling

Abstract

Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFα, IL-1β, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFα-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFα-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFα-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases.

Circulating PAMM, a novel antioxidant and anti-inflammatory protein, is elevated in acute SCI

“…This suppression was shown to be partially dependent upon the antiredox activity of PAMM [11]. Not only does PAMM inhibit responses of macrophages and endothelial cells to inflammatory stimuli, but its expression in human atheromatous tissue was nearly 3-fold as compared to normal, reflecting its potential as a therapeutic anti-inflammatory agent for the treatment of vascular inflammatory diseases [11]. The anti-redox activity of PAMM likely also inhibits TNFα-induced MAPK and NF-kB activation through a reduction in ER stress by promoting protein folding and secretion [11].…”

“…PAMM exerts its biological activity by inhibiting signal transduction pathways. However, the PAMM response to various stimuli varies, possibly due to the involvement of several different signaling pathways [11]. Regardless of the signal transduction pathways involved, the mechanism of PAMM action is dependent, at least in part, upon its anti-redox activity.…”

“…For example, PAMM negatively regulates cytokine-induced inflammatory responses in vascular endothelial cells by suppressing MAPK and NF-kB signal pathways. This suppression was shown to be partially dependent upon the antiredox activity of PAMM [11]. Not only does PAMM inhibit responses of macrophages and endothelial cells to inflammatory stimuli, but its expression in human atheromatous tissue was nearly 3-fold as compared to normal, reflecting its potential as a therapeutic anti-inflammatory agent for the treatment of vascular inflammatory diseases [11].…”

“…Not only does PAMM inhibit responses of macrophages and endothelial cells to inflammatory stimuli, but its expression in human atheromatous tissue was nearly 3-fold as compared to normal, reflecting its potential as a therapeutic anti-inflammatory agent for the treatment of vascular inflammatory diseases [11]. The anti-redox activity of PAMM likely also inhibits TNFα-induced MAPK and NF-kB activation through a reduction in ER stress by promoting protein folding and secretion [11]. We recently reported that mutations in the CXXC motif of PAMM suppress its anti-redox activity without suppressing the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages, indicating that PAMM's anti-inflammatory and anti-oxidant properties are independent [8].…”

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

“…New vascular genes not previously reported associated with total WMH, include the MAT1A gene, which catalyzes adenosine transfer from ATP to methionine and is associated with stroke and hypertension 59 . FAM213A encodes for the peroxiredoxin like 2A protein, which is an antioxidant associated with endothelial activation 60 . The CALCRL gene encodes the calcitonin receptor like receptor and modulates the calcitonin signaling system, implicated in ischemic stroke 61 .…”