Krüppel-like factor 4-mediated smooth muscle cell phenotype switching to a galectin-3 positive subclass is a detrimental event in the pathogenesis of atherosclerotic cardiovascular disease

© Non-coding RNA Investigation. All rights reserved. Non-coding RNA Investig 2020;4:8 | http://dx.doi. org/10.21037/ncri-20-7 Cardiovascular diseases such as coronary artery disease, myocardial infarction and stroke are considered the major cause of death worldwide. Atherosclerosis, narrowing of the arterial lumen due to accumulation of cholesterol within the vessel wall, represents the primary underlying pathology of cardiovascular diseases (1). Cholesterol lowering treatments are currently the first choice therapy for human subjects at risk of developing cardiovascular disease given that hypercholesterolemia is an established risk factor for the development lipid-laden macrophage foam cells, a decisive step in the formation of atherosclerotic lesions. Unfortunately, statin-induced lipid lowering is only able to achieve a 15–25% risk reduction in cardiovascular disease event rate (2,3). As such, there remains a clear need to uncover additional means to battle the occurrence of atherosclerotic cardiovascular disease. Although cholesterol accumulation in macrophages is a hallmark of atherosclerosis, many other cell types have also been suggested to play a role in the initial development and progression towards more advanced atherosclerotic lesions. These include cells from the innate and adaptive immune system, i.e., T and B cells, neutrophils, and mast cells as well as smooth muscle cells (1). However, the relative contribution of each individual cell type to the atherosclerosis pathology and overall cardiovascular disease outcome is not well understood. In the paper by Alencar et al. published in the journal Circulation in July 2020 (4), the authors have tried to provide novel insight in the specific role of smooth muscle cells in atherosclerosis. In detail, through combining novel and earlier established gene editing approaches in mice with state-of-the-art single cell RNA sequencing and plaque visualization methods, the authors have tested the hypothesis that smooth muscle cells can obtain different phenotypes within the atherosclerotic lesion context and that the different smooth muscle cell subtypes also differentially impact on the pathology. Using unbiased RNA sequencing it was found by Alencar et al. that 14 different cell clusters are present in advanced atherosclerotic lesions from both mice and humans and that the smooth muscle cell clusters overlap significantly between the two species with regard to their functional classification (4). Recently published RNA sequencing studies by Depuydt et al. have similarly identified 14 distinct cell populations in human carotid atherosclerotic plaques. They also observed that—besides smooth muscle cells— human atherosclerotic lesions indeed contain endothelial cells, mast cells, B cells, myeloid cells (monocytes/ macrophages), and T cells (5). An interesting aspect of the studies by Alencar et al. was that they could trace back the cellular origin of individual cell clusters through the use of lineage-specific fluorescent reporters. More specifically, it was revealed that 7 out of the total 14 cell populations in murine atherosclerotic plaques are actually derived from smooth muscle cells (4). Only 3 of these 7 specific cell clusters—however—displayed a relative Editorial Commentary