Abstract
Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (EphA2), vascular cell adhesion molecule-1 (VCAM-1), and Hcy in patients with arteriosclerosis and investigate their functions in Hcy-injured human umbilical vein endothelial cells (HUVECs). EphA2 knockdown was induced in HUVECs by shRNA lentivirus infection with EphA2-RNAi, and bulk RNA-seq assay was performed. Then we investigated the mechanism underlying the effect of recombinant human PGRN (rhPGRN) combined with shRNA interference of EphA2 on cell proliferation, migration, and angiogenesis in Hcy-injured HUVECs. Results showed that serum EphA2, VCAM-1, and Hcy levels in acute coronary syndrome patients were significantly higher than those in chronic coronary syndrome patients (p = 0.000; p = 0.000; p = 0.033, respectively). In vitro, we demonstrated that knockdown of EphA2 significantly impaired cell adhesion and inhibited HUVECs migration and angiogenesis (p < 0.001), which was associated with reduction in VCAM1 and VE-cadherin (p < 0.05). Hcy modulated the expression of PGRN and EphA2 in a time-and dose-dependent manner. However, rhPGRN ameliorated the Hcy-induced reduction in cell viability and migration (p < 0.05). Mechanistically, we found that PGRN/EphA2 and its downstream AKT/NF-κB signaling might be the primary signal transduction pathways underlying Hcy-induced injury. The present study illustrated that PGRN plays a previously unrecognized role in Hcy-induced endothelial injury, which is achieved through its interaction with EphA2 signaling, implying a promising therapeutic target for cardiovascular disease.
Highlights
Hyperhomocysteinemia (HHcy) is considered a significant and independent risk factor for cardiovascular disease (CVD), stroke, and neurodegenerative disease (Clarke et al, 1991; Veeranna et al, 2011; Shi et al, 2015; Moretti and Caruso, 2019)
We demonstrated that knockdown of Eph-receptor tyrosine kinase-type A2 (EphA2) significantly impaired cell adhesion and inhibited human umbilical vein endothelial cells (HUVECs) migration and angiogenesis (p < 0.001), which was associated with reduction in vascular cell adhesion molecule-1 (VCAM1) and VE-cadherin (p < 0.05)
(3) The progranulin/EphA2 axis might be the primary mechanism by which Hcy impairs endothelial adhesion and angiogenesis
Summary
Hyperhomocysteinemia (HHcy) is considered a significant and independent risk factor for cardiovascular disease (CVD), stroke, and neurodegenerative disease (Clarke et al, 1991; Veeranna et al, 2011; Shi et al, 2015; Moretti and Caruso, 2019). Reduced progression to advanced atherosclerotic plaques in EphA2(−/−)ApoE(−/−) mice suggests that EphA2 has an essential function in the early stage of cardiovascular disease (Neill et al, 2016; Cui et al, 2019). Previous studies have demonstrated the potential effect of EphA2 and PGRN in altering vascular permeability and the inflammatory response in lung injury (Guo et al, 2012; Hong et al, 2015). Whether PGRN and EphA2 are involved in vascular endothelial impairment induced by HHcy remains elucidated. This study aimed to investigate the levels of EphA2, PGRN, and Hcy in arteriosclerosis patients and to evaluate how PGRN and EphA2 exert their function in EC with Hcy-induced injury
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
