Novel Adipokine, FAM19A5, Inhibits Neointima Formation After Injury Through Sphingosine-1-Phosphate Receptor 2

Circulation. 2018 Jul 3;138(1):48-63. doi: 10.1161/CIRCULATIONAHA.117.032398.

Yingbao Wang ¹, Dixin Chen ¹ ², Yan Zhang ², Pingzhang Wang ² ³, Can Zheng ², Songyang Zhang ¹, Bing Yu ¹, Lu Zhang ¹, Guizhen Zhao ¹, Baihui Ma ¹, Zeyu Cai ¹, Nan Xie ¹, Shiyang Huang ², Ziyi Liu ¹, Xiaoning Mo ³, Youfei Guan ⁴, Xian Wang ¹, Yi Fu ¹, Dalong Ma ² ³, Ying Wang ⁵ ³, Wei Kong ⁶

Affiliations

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 [email protected] [email protected].
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.) [email protected] [email protected].

PMID: 29453251 DOI: 10.1161/CIRCULATIONAHA.117.032398

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 (K_d) 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.

Keywords

FAM19A5; S1PR2; VSMC; adipokine; neointima formation.

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