Letter by Wang et al Regarding Article, "Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis".

Circulation. 2019;140:e812–e813. DOI: 10.1161/CIRCULATIONAHA.119.043075 e812 *Drs Wang, Yang, and Chen contributed equally. Daxin Wang, MD* Xinquan Yang, MD* Tian Chen, MD* To the Editor: We have read with great interest the article by Bandaru et al,1 in a recent issue of Circulation, in which they have identified the filamin A (FLNA) cleavage mechanism in macrophages as a potential target to reduce inflammation and atherosclerotic plaque development. Previously, Bennett et al2 reviewed phenotypic modulation of multiple distinct smooth muscle cells (SMCs) in response to atherogenic stimuli such as proinflammatory dysfunctional macrophage-like phenotype, extracellular matrix–producing synthetic-SMC phenotype, and mesenchymal stem cell–like population. Recently, Wirka et al3 found that SMCs can undergo phenotypic modulation to exhibit novel fibroblast-like phenotype (eg, fibromyocyte) through regulating transcription factor 21 expression levels during atherosclerosis. Moreover, higher levels of transcription factor 21 expression were found to be associated with decreased risk for coronary artery disease in humans, and loss of transcription factor 21 resulted in fewer fibromyocytes in the lesion and at the protective fibrous cap, indicating the protective effects of phenotypic modulation of SMCs on the stability of atherosclerotic plaque in atherosclerosis. Apart from the authors’ findings of increased FLNA expression in human macrophages in advanced atherosclerotic plaques, we have also noticed that, compared with human intimal thickening of intermediate atherosclerotic lesions, the number of FLNA-expressing SMCs within the advanced atherosclerotic plaques decreased significantly. Considering the intimal SMCs contributing to the foam cell population in arterial plaque and the crucial role of FLNA in the migration of SMCs,2,4 we wonder whether the change in FLNA expression in SMCs could be associated with its plasticity during the progression of atherosclerosis. Based on this understanding, we suggest that further investigation of differential distribution and transdifferentiation of SMCs expressing FLNA in arterial lesion or the change in cholesterol metabolism in such SMCs within pathological intima at different stages of atherosclerosis might provide valuable insights regarding identifying the role of FLNA in activation of macrophages and SMCs and interaction between the two. This understanding may be helpful in explaining the great reduction of aortic atherosclerotic plaques in mice lacking FLNA in macrophages or mice treated with calpeptin. Although 8-week calpeptin treatment in an atherosclerosis model could reduce atherosclerotic plaque formation with no obvious signs of adverse reaction, we believe that further long-term studies aimed at evaluating the balance between impaired macrophage function induced by calpeptin and the process of innate immunity, normal tissue development, homeostasis, and repair of damaged tissue should be carried out for favoring its clinic utility.5