Yingbao Wang1, Dixin Chen1,2, Yan Zhang2, Pingzhang Wang2,3, Can Zheng2, Songyang Zhang1, Bing Yu1, Lu Zhang1, Guizhen Zhao1, Baihui Ma1, Zeyu Cai1, Nan Xie1, Shiyang Huang2, Ziyi Liu1, Xiaoning Mo3, Youfei Guan4, Xian Wang1, Yi Fu1, Dalong Ma2,3, Ying Wang5,3, Wei Kong6. 1. Department of Physiology and Pathophysiology (Y.W., D.C., S.Z., B.Y., L.Z., G.Z., B.M., Z.C., N.X., Z.L., X.W., Y.F., W.K.). 2. Department of Immunology, Key Laboratory of Medical Immunology of Ministry of Health (D.C., Y.Z., P.W., C.Z., S.H., D.M., Y.W.), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. 3. Center for Human Disease Genomics, Peking University, Beijing, China (P.W., X.M., D.M., Y.W.). 4. Advanced Institute for Medical Sciences, Dalian Medical University, Liaoning, China (Y.G.). 5. Department of Immunology, Key Laboratory of Medical Immunology of Ministry of Health (D.C., Y.Z., P.W., C.Z., S.H., D.M., Y.W.), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China kongw@bjmu.edu.cn yw@bjmu.edu.cn. 6. Department of Physiology and Pathophysiology (Y.W., D.C., S.Z., B.Y., L.Z., G.Z., B.M., Z.C., N.X., Z.L., X.W., Y.F., W.K.) kongw@bjmu.edu.cn yw@bjmu.edu.cn.
Abstract
BACKGROUND: Obesity plays crucial roles in the development of cardiovascular diseases. However, the mechanisms that link obesity and cardiovascular diseases remain elusive. Compelling evidence indicates that adipokines play an important role in obesity-related cardiovascular diseases. Here, we found a new adipokine-named family with sequence similarity 19, member A5 (FAM19A5), a protein with unknown function that was predicted to be distantly related to the CC-chemokine family. We aimed to test whether adipose-derived FAM19A5 regulates vascular pathology on injury. METHODS: DNA cloning, protein expression, purification, and N-terminal sequencing were applied to characterize FAM19A5. Adenovirus infection and siRNA transfection were performed to regulate FAM19A5 expression. Balloon and wire injury were performed in vivo on the rat carotid arteries and mouse femoral arteries, respectively. Bioinformatics analysis, radioactive ligand-receptor binding assays, receptor internalization, and calcium mobilization assays were used to identify the functional receptor for FAM19A5. RESULTS: We first characterized FAM19A5 as a secreted protein, and the first 43 N-terminal amino acids were the signal peptides. Both FAM19A5 mRNA and protein were abundantly expressed in the adipose tissue but were downregulated in obese mice. Overexpression of FAM19A5 markedly inhibited vascular smooth muscle cell proliferation and migration and neointima formation in the carotid arteries of balloon-injured rats. Accordingly, FAM19A5 silencing in adipocytes significantly promoted vascular smooth muscle cell activation. Adipose-specific FAM19A5 transgenic mice showed greater attenuation of neointima formation compared with wild-type littermates fed with or without Western-style diet. We further revealed that sphingosine-1-phosphate receptor 2 was the functional receptor for FAM19A5, with a dissociation constant (Kd) of 0.634 nmol/L. Inhibition of sphingosine-1-phosphate receptor 2 or its downstream G12/13-RhoA signaling circumvented the suppressive effects of FAM19A5 on vascular smooth muscle cell proliferation and migration. CONCLUSIONS: We revealed that a novel adipokine, FAM19A5, was capable of inhibiting postinjury neointima formation via sphingosine-1-phosphate receptor 2-G12/13-RhoA signaling. Downregulation of FAM19A5 during obesity may trigger cardiometabolic diseases.
BACKGROUND:Obesity plays crucial roles in the development of cardiovascular diseases. However, the mechanisms that link obesity and cardiovascular diseases remain elusive. Compelling evidence indicates that adipokines play an important role in obesity-related cardiovascular diseases. Here, we found a new adipokine-named family with sequence similarity 19, member A5 (FAM19A5), a protein with unknown function that was predicted to be distantly related to the CC-chemokine family. We aimed to test whether adipose-derived FAM19A5 regulates vascular pathology on injury. METHODS: DNA cloning, protein expression, purification, and N-terminal sequencing were applied to characterize FAM19A5. Adenovirus infection and siRNA transfection were performed to regulate FAM19A5 expression. Balloon and wire injury were performed in vivo on the rat carotid arteries and mouse femoral arteries, respectively. Bioinformatics analysis, radioactive ligand-receptor binding assays, receptor internalization, and calcium mobilization assays were used to identify the functional receptor for FAM19A5. RESULTS: We first characterized FAM19A5 as a secreted protein, and the first 43 N-terminal amino acids were the signal peptides. Both FAM19A5 mRNA and protein were abundantly expressed in the adipose tissue but were downregulated in obesemice. Overexpression of FAM19A5 markedly inhibited vascular smooth muscle cell proliferation and migration and neointima formation in the carotid arteries of balloon-injured rats. Accordingly, FAM19A5 silencing in adipocytes significantly promoted vascular smooth muscle cell activation. Adipose-specific FAM19A5transgenic mice showed greater attenuation of neointima formation compared with wild-type littermates fed with or without Western-style diet. We further revealed that sphingosine-1-phosphate receptor 2 was the functional receptor for FAM19A5, with a dissociation constant (Kd) of 0.634 nmol/L. Inhibition of sphingosine-1-phosphate receptor 2 or its downstream G12/13-RhoA signaling circumvented the suppressive effects of FAM19A5 on vascular smooth muscle cell proliferation and migration. CONCLUSIONS: We revealed that a novel adipokine, FAM19A5, was capable of inhibiting postinjury neointima formation via sphingosine-1-phosphate receptor 2-G12/13-RhoA signaling. Downregulation of FAM19A5 during obesity may trigger cardiometabolic diseases.
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