AUTHOR=Huan Wei , Yandong Liu , Chao Wang , Sili Zou , Jun Bai , Mingfang Liao , Yu Chen , Lefeng Qu 

TITLE=YKL-40 Aggravates Early-Stage Atherosclerosis by Inhibiting Macrophage Apoptosis in an Aven-dependent Way

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.752773

DOI=10.3389/fcell.2021.752773

ISSN=2296-634X

ABSTRACT=<p><bold>Objective:</bold> programmed cell removal in atherosclerotic plaques plays a crucial role in retarding lesion progression. Macrophage apoptosis has a critical role in PrCR, especially in early-stage lesions. YKL-40 has been shown to be elevated as lesions develop and is closely related to macrophages. This study aimed to determine the effect of YKL-40 on regulating macrophage apoptosis and early-stage atherosclerosis progression.</p><p><bold>Research design and Methods:</bold> The correlations among the expression level of YKL-40, the area of early-stage plaque, and the macrophage apoptosis rate in plaques have been shown in human carotid atherosclerotic plaques through pathological and molecular biological detection. These results were successively confirmed <italic>in vivo</italic> (<italic>Ldlr</italic><sup>−/-</sup> mice treated by YKL-40 recombinant protein/neutralizing antibody) and <italic>in vitro</italic> (macrophages that <italic>Ykl40</italic> up-/down-expressed) experiments. The downstream targets were predicted by iTRAQ analysis.</p><p><bold>Results:</bold> In early-stage human carotid plaques and murine plaques, the YKL-40 expression level had a significant positive correlation with the area of the lesion and a significant negative correlation with the macrophage apoptosis rate. <italic>In vivo</italic>, the plaque area of aortic roots was significantly larger in the recomb-YKL-40 group than that in IgG group (<italic>p</italic> = 0.0247) and was significantly smaller in the anti-YKL-40 group than in the IgG group (<italic>p</italic> = 0.0067); the macrophage apoptosis rate of the plaque in aortic roots was significantly lower in the recomb-YKL-40 group than that in IgG group (<italic>p</italic> = 0.0018) and was higher in anti-YKL-40 group than that in VC group. <italic>In vitro</italic>, the activation level of caspase-9 was significantly lower in RAW264.7 with <italic>Ykl40</italic> overexpressed than that in controls (<italic>p</italic> = 0.0054), while the expression level of Aven was significantly higher than that in controls (<italic>p</italic> = 0.0031). The apoptosis rate of RAW264.7 treated by recomb-YKL40 was significantly higher in the <italic>Aven</italic> down-regulated group than that in the control group (<italic>p</italic> &lt; 0.001). The apoptosis inhibitor Aven was confirmed as the target molecule of YKL-40. Mechanistically, YKL-40 could inhibit macrophage apoptosis by upregulating Aven to suppress the activation of caspase-9.</p><p><bold>Conclusion:</bold> YKL-40 inhibits macrophage apoptosis by upregulating the apoptosis inhibitor Aven to suppress the activation of caspase-9, which may impede normal PrCR and promote substantial accumulation in early-stage plaques, thereby leading to the progression of atherosclerosis.</p>