SRY Gene Transferred by Extracellular Vesicles Accelerates Atherosclerosis by Promotion of Leukocyte Adherence to Endothelial Cells

To study if and how SRY (sex determining region, Y) DNAs in plasma extracellular vesicle (EVs) is involved in the pathogenesis of atherosclerosis. PCR and gene sequencing found SRY gene fragment in plasma EVs from male but not from female patients; EVs from male patients with coronary artery disease (CAD) had higher SRY gene copy number (GCN) than healthy subjects. Additional studies found that leukocytes, 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 HEK293 cells, monocytes (THP-1) and endothelial cells (HUVECs), which do not endogenously express SRY protein, were found to express newly-synthesized SRY protein. This resulted in an increase in adherence factors, CD11-a in THP-1 cells and ICAM-1 in HUVECs. Electrophoretic mobility shift assay 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. SRYDNAs transferred from EVs have pathophysiological significance in vivo; injection of SRY EVs to ApoE-/- 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.
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research