Cold-inducible RNA-binding protein plays a central role in the pathogenesis of abdominal aortic aneurysm in a murine experimental model

Abstract

Cold-inducible RNA-binding protein (CIRP) is a recently identified proinflammatory cytokine. We hypothesize that CIRP is involved in the progression of abdominal aortic aneurysms (AAA) and that anti-CIRP treatment could inhibit this progression. We investigated CIRP expression in the sera and aneurysmal tissues of human AAA patients and elastase-induced AAA rats. To further examine the role of CIRP in the development of AAA, anti-CIRP antibody (1mg/kg) or nonimmunized control immunoglobulin (Ig)G (1mg/kg) was injected via the caudal vein in the experimental AAA model. To further investigate the underlying mechanisms, RAW 267.4cells were stimulated with recombinant murine CIRP (rmCIRP). In human AAA tissue, CIRP exhibited a 5.6-fold and 93% increase in mRNA and protein expression, respectively. In a rat AAA model, CIRP was upregulated significantly in a time-dependent manner in the serum and AAA tissue. The anti-CIRP antibody treatment significantly suppressed the dilation of experimental AAA. Simultaneously, inhibition of CIRP significantly attenuated the expression of matrix metalloproteinase (MMP)-2, MMP-9, tumor necrosis factor-α, and monocyte chemoattractant protein-1, and the number of CD68-positive macrophages in the experimental AAA tissue. Invitro, rmCIRP significantly increased MMP-9 messenger RNA expression in a dose-dependent manner by 1.2-fold, 2.9-fold, and 5.5-fold, respectively. Simultaneously, rmCIRP promoted RAW 264.7cell migration, with an approximately 2.7-fold increase in the number of migrated cells. Our findings demonstrate that CIRP mediates experimental AAA development by promoting the inflammatory response and inducing MMP-9 expression, demonstrating its potential as a novel target for inhibiting the progression of AAA.