Response by Owens and Deaton to Letter Regarding Article, "Dichotomous Roles of Smooth Muscle Cell-Derived MCP1 (Monocyte Chemoattractant Protein 1) in Development of Atherosclerosis".
Response by Owens and Deaton to Letter Regarding Article, "Dichotomous Roles of Smooth Muscle Cell-Derived MCP1 (Monocyte Chemoattractant Protein 1) in Development of Atherosclerosis".
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Owens 和 Deaton 对有关文章“平滑肌细胞衍生的 MCP1（单核细胞趋化蛋白 1）在动脉粥样硬化发展中的二分作用”的信件的回应。
DOI：
10.1161/atvbaha.122.318638
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Deaton,RebeccaA
中科院分区：
文献类型：
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作者：
Owens,GaryK;Deaton,RebeccaA
We thank Wang et al for their kind remarks and further insights regarding our Owsiany et al1 2022 Arteriosclerosis, Thrombosis, and Vascular Biology article. We fully agree with virtually all their comments including there being multiple possible cellular sources of MCP1 (monocyte chemoattractant protein 1) and secondary responses to its knockout in smooth muscle cells (SMC) including activating other cytokines. As is the case with any gene knockout study, the phenotype observed is a function not only of the initial gene knockout but also any downstream adaptive and maladaptive responses. Our observation that SMC heterozygous, but not homozygous MCP1 knockout mice, showed a paradoxical increase in plaque size and macrophage content is consistent with this idea since the homozygous SMC MCP1 knockout mice are more likely to undergo compensatory changes. Moreover, these results unveiled an unexpected beneficial role of SMC-derived MCPI in a Western diet–fed Apoe−/− mouse model. We present evidence, but certainly not proof, that this phenotype may be the result of systemic monocytosis secondary to loss of SMC-derived MCP1 causing increased release of monocytes from hematopoietic stem cell niches. However, as indicated by Wang et al, there are numerous other possibilities that remain to be tested. One interesting possibility is that initial production of MCP1 by SMC is beneficial because it promotes recruitment of monocytes-macrophages to early-stage atherosclerotic lesions as a means to remove oxidized lipids and apoptotic cells. However, as suggested by Randolph, 2 the process may only be effective for a short time before the macrophages are overwhelmed, become engorged with lipids, fail to egress to the lymphatics, and give rise to foam cells and contribute to a chronic inflammatory state. We also agree with their comment that there is stage-specific regulation due to the different cellular sources of MCP1 at different stages of atherosclerosis. In support of this idea, we observed that mice withMCP1 knockout in the subset of SMC that have transitioned through a Lgals3 (Galectin3)+ state exhibit a phenotype virtually opposite to that of mice with MCP1 knockout in all SMC. SMC-Lgals3 dual recombinase MCP1 knockout mice had lesions with an increased ACTA2 (smooth muscle alpha-actin)+ 2 fibrous cap and decreased investment of Lgals3-transitioned SMCs, consistent with increased plaque stability. That is, MCP1 expression by this subset of SMC appears to be detrimental.
影响因子：
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作者：
S. Burley;G. Petsko
通讯作者：
S. Burley;G. Petsko