Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway

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.

Plasma Homocysteine Level Is Independently Associated With Conventional Atherogenic Lipid Profile and Remnant Cholesterol in Adults

“…Plasma Hcy is an independent risk factor for ASCVD ( 33 – 36 ). Nevertheless, the mechanism linking Hcy to cardiovascular disease is not fully understood.…”

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

“…In particular, AβQ22 significantly inhibited angiogenesis already at the concentration of 1 μM. Hcy has been observed to disrupt angiogenic capabilities of HUVEC ECs; however, it is not established if it can affect cerebral angiogenesis (Pan et al., 2017 ; Tian et al., 2020 ; Zhang et al., 2012 ). To determine whether Hcy promotes angiogenic deficits in cerebral ECs and whether combined challenge of HCMECs with AβQ22 and Hcy additively decreases HCMECs angiogenic capability, we performed an angiogenesis inhibition assay.…”

Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration

“…2F ). High-frequency upregulated TDEGs included Plet1 and Sfn that were highly correlated with epithelial cell differentiation ( Kondo et al, 2002 ; Hammond et al, 2012 ; Gunnarsson et al, 2016 ) and vasculature development-related genes Pxdc1 and Epha2 ( Tian et al, 2020 ; Zhang et al, 2021a ). The consistently downregulated TDEGs Apoe and Dapl1 were both reported to be involved in the positive regulation of cell death ( Kobayashi and Yonehara, 2009 ; Medkour et al, 2017 ; Martins Cardoso et al, 2019 ) ( Fig.…”