Fibulin-3 affects vascular endothelial function and is regulated by angiotensin II

Objective: The aim of the present study was to investigate the effect of fibulin-3 on vascular endothelial function, and to explore the relevant underlying mechanism with regard to the involvement of angiotensin II (AngII).

Methods: One hundred and eight patients with essential hypertension (EH) and 31 controls were included to measure the flow-mediated dilatation (FMD). Serum fibulin-3 and AngII were examined using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay. Stable transfection of fibulin-3 was conducted on human umbilical vein endothelial cells (HUVECs) and SV40T-transformed HUVECs (PUMC-HUVEC-T1 cells). Cell counting kit-8 assay, cell cycle assay, wound healing assay, Transwell assay, Apoptosis assay, and tube formation assay were subsequently performed. The expression of angiogenesis-associated genes [endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor A (VEGFA)] were measured by western blot analysis. HUVECs and PUMC-HUVEC-T1 cells were treated with AngII, and with or without an inhibitor of nuclear factor κB (NF-κB), BAY 11-7082. Pro-inflammatory cytokines [interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)] were detected by ELISA. The expression levels of fibulin-3 and p65 were then measured by western blotting.

Results: Lower levels of serum fibulin-3 were accompanied by poorer FMD and higher levels of serum AngII in patients with EH. Fibulin-3 overexpression promoted cell proliferation, migration, and angiogenesis, but led to an inhibition of Apoptosis. By contrast, fibulin-3 downregulation inhibited cell proliferation, migration and angiogenesis, but promoted Apoptosis. AngII induced inflammation and inhibited the expression of fibulin-3. BAY 11-7082 eliminated the inhibitory effect of AngII on fibulin-3.

Conclusions: Taken together, the results of the present study have shown that serum fibulin-3 may be a predictor of vascular endothelial function in patients with EH. Fibulin-3 gene may also have a beneficial role in repairing the vascular endothelium. Furthermore, the results also suggested that fibulin-3 gene was suppressed by AngII via the NF-κB signaling pathway.