Identification of Mep1a as a susceptibility gene for atherosclerosis in mice
Identification of Mep1a as a susceptibility gene for atherosclerosis in mice
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DOI：
10.1093/genetics/iyab160
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发表时间：
2021-09-29
期刊：
影响因子：
3.3
通讯作者：
Shi, Weibin
中科院分区：
文献类型：
--
作者：
Grainger, Andrew T.;Pilar, Nathanael;Shi, Weibin
动脉粥样硬化是心脏病发作、缺血性中风和外周动脉疾病的根本原因，涉及的遗传因素大多尚未确定。我们以前确定了一个显着的位点，小鼠17号染色体上的动脉粥样硬化，Ath 49，在BALB/c和SM株之间的互交。Ath 49在置信区间中与AKR x DBA/2互交中映射的Ath 22部分重叠。生物信息学分析优先考虑Mep 1a，编码meprin 1 α金属内肽酶，作为Ath 49的可能候选基因。为了证明因果关系，制备了Mep 1a（-/-）Apoe（-/-）小鼠，并与Mep 1a（-/-）Apoe（-/-）小鼠进行动脉粥样硬化发展比较。Mep 1a在动脉粥样硬化病变中大量表达，而在健康小鼠的主动脉和肝脏中不表达。Mep 1a（-/-）Apoe（-/-）小鼠在早期和晚期病变大小方面均表现出显著减少。Mep 1a的缺失导致坏死减少，但在晚期病变中增加了巨噬细胞和中性粒细胞含量，降低了CXCL 5和氧化应激生物标志物的血浆水平。此外，Mep 1a（-/-）小鼠在普通饲料中的甘油三酯水平显著降低。因此，Mep 1a是动脉粥样硬化的易感基因，并部分通过氧化应激和炎症作用来促进动脉粥样硬化。
Atherosclerosis is the underlying cause of heart attack, ischemic stroke and peripheral arterial disease, and genetic factors involved remain mostly unidentified. We previously identified a significant locus on mouse chromosome 17 for atherosclerosis, Ath49, in an intercross between BALB/c and SM strains. Ath49 partially overlaps in the confidence interval with Ath22 mapped in an AKR x DBA/2 intercross. Bioinformatics analysis prioritized Mep1a, encoding meprin 1 alpha metalloendopeptidase, as a likely candidate gene for Ath49. To prove causality, Mep1a(-/-)Apoe(-/-) mice were generated and compared with Mep1a(-/-)Apoe(-/- )mice for atherosclerosis development. Mep1a was found abundantly expressed in atherosclerotic lesions but not in healthy aorta and liver of mice. Mep1a(-/-)Apoe(-/-) mice exhibited significant reductions in both early and advanced lesion sizes. Loss of Mep1a led to decreased necrosis but increased macrophage and neutrophil contents in advanced lesions, reduced plasma levels of CXCL5 and an oxidative stress biomarker. In addition, Mep1a(-/-) mice had significantly reduced triglyceride levels on a chow diet. Thus, Mep1a is a susceptibility gene for atherosclerosis and aggravates atherosclerosis partially through action on oxidative stress and inflammation.