Caiying Tang, Guoxia Shi, Ruyi Jia, Xueying Pei, Chao Wang, Zhuo Du, Song Li, Pingping Wan, Sibo Sun, Cong Peng, Shuang Li, Ping Sun, Bo Yu, Jiannan Dai
{"title":"慢性血流紊乱通过 DNA 甲基转移酶依赖性内皮细胞向间质转化诱导表层侵蚀性病变","authors":"Caiying Tang, Guoxia Shi, Ruyi Jia, Xueying Pei, Chao Wang, Zhuo Du, Song Li, Pingping Wan, Sibo Sun, Cong Peng, Shuang Li, Ping Sun, Bo Yu, Jiannan Dai","doi":"10.5551/jat.64990","DOIUrl":null,"url":null,"abstract":"<p><strong>Aim: </strong>Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.</p><p><strong>Methods: </strong>We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.</p><p><strong>Results: </strong>Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.</p><p><strong>Conclusions: </strong>Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.</p>","PeriodicalId":15128,"journal":{"name":"Journal of atherosclerosis and thrombosis","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chronic Disturbed Flow Induces Superficial Erosion-Prone Lesion via Endothelial-to-Mesenchymal Transition in a DNA Methyltransferase-Dependent Manner.\",\"authors\":\"Caiying Tang, Guoxia Shi, Ruyi Jia, Xueying Pei, Chao Wang, Zhuo Du, Song Li, Pingping Wan, Sibo Sun, Cong Peng, Shuang Li, Ping Sun, Bo Yu, Jiannan Dai\",\"doi\":\"10.5551/jat.64990\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.</p><p><strong>Methods: </strong>We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.</p><p><strong>Results: </strong>Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.</p><p><strong>Conclusions: </strong>Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.</p>\",\"PeriodicalId\":15128,\"journal\":{\"name\":\"Journal of atherosclerosis and thrombosis\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2024-11-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of atherosclerosis and thrombosis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.5551/jat.64990\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of atherosclerosis and thrombosis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5551/jat.64990","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
Chronic Disturbed Flow Induces Superficial Erosion-Prone Lesion via Endothelial-to-Mesenchymal Transition in a DNA Methyltransferase-Dependent Manner.
Aim: Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.
Methods: We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.
Results: Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.
Conclusions: Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.