SRY gene transferred by extracellular vesicles accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells.

We set out to investigate whether and how SRY (sex-determining region, Y) DNAs in plasma EVs (extracellular vesicles) is involved in the pathogenesis of atherosclerosis. PCR and gene sequencing found the SRY gene fragment in plasma EVs from male, but not female, patients; EVs from male patients with CAD (coronary artery disease) had a higher SRY GCN (gene copy number) than healthy subjects. Additional studies found that leucocytes, the major source of plasma EVs, had higher SRY GCN and mRNA and protein expression in male CAD patients than controls. After incubation with EVs from SRY -transfected HEK (human embryonic kidney)-293 cells, monocytes (THP-1) and HUVECs (human umbilical vein endothelial cells), which do not endogenously express SRY protein, were found to express newly synthesized SRY protein. This resulted in an increase in the adherence factors CD11-a in THP-1 cells and ICAM-1 (intercellular adhesion molecule 1) in HUVECs. EMSA showed that SRY protein increased the promoter activity of CD11-a in THP-1 cells and ICAM-1 in HUVECs. There was an increase in THP-1 cells adherent to HUVECs after incubation with SRY-EVs. SRY DNAs transferred from EVs have pathophysiological significance in vivo ; injection of SRY EVs into ApoE−/− (apolipoprotein-knockout) mice accelerated atherosclerosis. The SRY gene in plasma EVs transferred to vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis; this mechanism provides a new approach to the understanding of inheritable CAD in men. Abbreviations: ApoE−/−, apolipoprotein E-knockout; AT1R, angiotensin type 1 receptor; BCECF, 2′,7′-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein; BCECF/AM, BCECF acetoxymethyl ester; CAD, coronary artery disease; CML, chronic myeloid leukaemia; CMV, cytomegalovirus; EV, extracellular vesicle; GCN, gene copy number; HEK, human embryonic kidney; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule 1; RT, reverse transcription; SRY, sex-determining region, Y