Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2 pathway

Currently, no mouse models manifest calcification and thrombus formation, which is frequently associated with human atherosclerosis. We demonstrated that lack of Favine/CCDC3 in apoE knockout mice accelerated atherosclerosis accompanied by large cholesterol crystals and calcification, and also promoted thrombus formation in the left ventricle and arteries. Circulating Favine was detectable in WT mouse lasma. RNA-sequencing analysis of aortae in DKO mice showed similar gene expression patterns of human atherosclerosis with unstable and vulnerable plaques. Importantly, human FAVINE mRNA expressions were lower in atheroma plaque than in adjacent intact aortic tissue and decreased with the progression of atherosclerosis. Pathway analysis of aortae in DKO mice suggested the decrease of the MEF2C-KLF2-mediated transcriptional pathway. Favine insufficiency and its attenuated downstream pathways may increase atherosclerosis progression with calcification and thrombus, which have not previously been fully modeled in experimental animals. Favine and its downstream pathways may have therapeutic potential for atherosclerosis. To investigate the mechanisms of progression of atherosclerosis, calcification, and thrombosis in DKO mice, bulk RNA-seq analysis of the aortas of ApoE KO mice and DKO was carried out.目前尚未有小鼠模型能够再现常与人类动脉粥样硬化相关的钙化与血栓形成表型。本研究证实，在载脂蛋白E敲除（apoE knockout）小鼠中敲除Favine/CCDC3可加速动脉粥样硬化进程，伴随大量胆固醇结晶与钙化形成，同时还会促进左心室及动脉内的血栓生成。野生型（WT）小鼠的血浆中可检测到循环型Favine。对双敲除（DKO）小鼠主动脉的RNA测序（RNA-sequencing）分析显示，其基因表达模式与存在不稳定易损斑块的人类动脉粥样硬化相似。值得注意的是，人类动脉粥样硬化斑块中的FAVINE mRNA表达水平低于邻近的完整主动脉组织，且随动脉粥样硬化的进展而进一步降低。对DKO小鼠主动脉的通路分析显示，MEF2C-KLF2介导的转录通路活性出现下调。Favine表达不足及其下游通路的弱化，可能会加剧伴随钙化与血栓形成的动脉粥样硬化进程，而此类表型此前尚未在实验动物中得到完整建模。Favine及其下游通路或可为动脉粥样硬化提供潜在治疗靶点。为探究DKO小鼠动脉粥样硬化、钙化及血栓形成的潜在机制，本研究对载脂蛋白E敲除（ApoE KO）小鼠与DKO小鼠的主动脉开展了批量RNA测序（bulk RNA-seq）分析。