AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis

Abstract

AIP1 (ASK1-interacting protein-1; encoded by the DAB2IP gene), a signaling scaffolding protein, is abundantly expressed in vascular endothelial cells (EC). While it was initially discovered as an apoptosis signal-regulating kinase 1 (ASK1)-interacting protein, AIP1 broadly suppresses inflammatory responses triggered by cytokines and stresses such as TNF, LPS, VEGF, and endoplasmic reticulum (ER) stress in EC (therefore, AIP1 is an anti-inflammatory protein). Human genome-wide association study (GWAS) has identified DAB2IP gene variants conferring susceptibility to cardiovascular diseases. Consistently, a global or vascular EC-specific deletion of DAB2IP in mice strongly enhances inflammatory responses and exacerbates atherosclerosis and graft arteriosclerosis progression in mouse models. Mechanisms for AIP1 function and regulation associated with human cardiovascular diseases need further investigations.

Fig.1. AIP1 limits atherogenic signaling in EC

Proinflammatory stimuli LPS and atherogenic stimuli oxLDL induce NF-κB signaling in EC, which drives expression of adhesion molecules on EC, mediating interactions of monocytes with EC during the initiation of atherosclerosis. AIP1 deletion in vascular EC augments LPS/TLR4 and oxLDL-induced NF-κB and JNK signaling, gene expression of adhesion molecules, chemokines and monocyte adhesion, leading augmented atherosclerosis progression.