Macrophage elastase derived from adventitial macrophages modulates aortic remodeling

Yajie Chen; Xiawen Yang; Shuji Kitajima; Longquan Quan; Yao Wang; Maobi Zhu; Enqi Liu; Liangxue Lai; Haizhao Yan; Jianglin Fan

doi:10.3389/fcell.2022.1097137

Macrophage elastase derived from adventitial macrophages modulates aortic remodeling

Front Cell Dev Biol. 2023 Jan 10:10:1097137. doi: 10.3389/fcell.2022.1097137. eCollection 2022.

Authors

Yajie Chen^{1

2}, Xiawen Yang¹, Shuji Kitajima³, Longquan Quan⁴, Yao Wang¹, Maobi Zhu¹, Enqi Liu⁵, Liangxue Lai^{1

6}, Haizhao Yan^{1

2

6}, Jianglin Fan^{1

2}

Affiliations

¹ Guangdong Province Key Laboratory, Southern China Institute of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China.
² Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
³ Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan.
⁴ College of Animal Science and Technology, China Agricultural University, Beijing, China.
⁵ Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, China.
⁶ Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.

Abstract

Abdominal aortic aneurysm (AAA) is pathologically characterized by intimal atherosclerosis, disruption and attenuation of the elastic media, and adventitial inflammatory infiltrates. Although all these pathological events are possibly involved in the pathogenesis of AAA, the functional roles contributed by adventitial inflammatory macrophages have not been fully documented. Recent studies have revealed that increased expression of matrix metalloproteinase-12 (MMP-12) derived from macrophages may be particularly important in the pathogenesis of both atherosclerosis and AAA. In the current study, we developed a carrageenan-induced abdominal aortic adventitial inflammatory model in hypercholesterolemic rabbits and evaluated the effect of adventitial macrophage accumulation on the aortic remodeling with special reference to the influence of increased expression of MMP-12. To accomplish this, we compared the carrageenan-induced aortic lesions of transgenic (Tg) rabbits that expressed high levels of MMP-12 in the macrophage lineage to those of non-Tg rabbits. We found that the aortic medial and adventitial lesions of Tg rabbits were greater in degree than those of non-Tg rabbits, with the increased infiltration of macrophages and prominent destruction of elastic lamellae accompanied by the frequent appearance of dilated lesions, while the intimal lesions were slightly increased. Enhanced aortic lesions in Tg rabbits were focally associated with increased dilation of the aortic lumens. RT-PCR and Western blotting revealed high levels of MMP-12 in the lesions of Tg rabbits that were accompanied by elevated levels of MMP-2 and -3, which was caused by increased number of macrophages. Our results suggest that adventitial inflammation constitutes a major stimulus to aortic remodeling and increased expression of MMP-12 secreted from adventitial macrophages plays an important role in the pathogenesis of vascular diseases such as AAA.

Keywords: MMP-12; abdominal aortic aneurysm; atherosclerosis; elastin; macrophage; transgenic rabbits.

Grants and funding

This work was supported the National Natural Science Foundation of China (No. 81941001, 82100482, and 82200504), National Key Research and Development Program of China (2022YFA1105403), Science and Technology Planning Project of Guangdong Province (2021A1515110916, 2020A1515110213, 2021A1515110008), and Innovation team program supported by Guangdong Province (2020KCXTD038). Application Foundation Project Support by Jiangmen City (2021030103170007301), Guangdong Province Key Program of Discipline (2021ZDJS091).