Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2 pathway
Sachiko Kobayashi,
Shunbun Kita,
Daisuke Okuzaki,
Yuya Fujishima,
Michio Otsuki,
Hisashi Kato,
Yasuko Nishizawa,
Kazuya Miyashita,
Chieko Yokoyama,
Atsunori Fukuhara,
Eiichi Morii,
Iichiro Shimomura
Affiliations
Sachiko Kobayashi
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Corresponding author
Shunbun Kita
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Corresponding author
Daisuke Okuzaki
Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Yuya Fujishima
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Michio Otsuki
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Endocrinology, Graduate School of Medical Science, Tokyo Women’s Medical University, Kawada-cho, Shinjuku-ku, Tokyo 162-8666 Tokyo, Japan
Hisashi Kato
Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Yasuko Nishizawa
Research Institute, Nozaki Tokushukai Hospital, 2-10-50 Tanigawa, Daitou, Osaka 574-0074, Japan
Kazuya Miyashita
Immuno-Biological Laboratories Co., Ltd., 1091-1 Naka, Fujioka, Gunma 375-0005, Japan
Chieko Yokoyama
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Nutrition and Life Science, Kanagawa Institute of Technology, 1030 Shimoogino, Atsugi, Kanagawa 243-0292, Japan
Atsunori Fukuhara
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Eiichi Morii
Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Iichiro Shimomura
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Summary: 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 plasma. 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.
