Aims
Neointima hyperplasia is the pathological basis of atherosclerosis and restenosis, which have been associated with diabetes mellitus (DM). Fibroblast growth factor 21 (FGF21) is a potential diabetic drug, however, it has not been investigated whether FGF21 prevents neointima hyperplasia in DM.
Background and aims
Neointima hyperplasia is the pathological basis of atherosclerosis and restenosis, which have been associated with diabetes mellitus (DM). Fibroblast growth factor 21 (FGF21) is a potential diabetic drug, however, it has not been investigated whether FGF21 prevents neointima hyperplasia in DM.
Conclusions
We demonstrated that potential protection of FGF21 on VSMCs proliferation and migration was associated with inhibition of FGFR1/Syk/NLRP3 inflammasome, resulting in the improvement of neointima hyperplasia in diabetic mice.
Methods
Vascular neointima hyperplasia was induced in mice fed a high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. In vitro, vascular smooth muscle cells (VSMCs) were incubated with high glucose (HG, 30 mM). VSMC proliferation and migration, as well as formation of NLRP3 inflammasome, were assessed.
Results
We found that FGF21 significantly inhibited neointima hyperplasia and improved endothelium-independent contraction in the wire-injured common carotid artery (CCA) of diabetic mice. In vitro, the proliferation and migration of HG-treated VSMCs were shown as remarkable increase of PCNA, cyclin D1, MMP2 and MMP9, as well as cell migration through wound healing and transwell migration assays. Such abnormal changes were dramatically reversed by FGF21, which mimicked the role of NLRP3 inflammasome inhibitor MCC950 and caspase-1 inhibitor WEHD. Moreover, along with more NLRP3, ASC oligomer and their colocalization, the release of active caspase-1(p20) and IL-1β was significantly inhibited by FGF21 in VSMCs exposed to HG. Furthermore, FGF21 suppressed phosphorylation of spleen tyrosine kinase (Syk) via FGFR1, which regulated NLRP3 inflammasome through ASC phosphorylation and oligomerization. Conclusions: We demonstrated that potential protection of FGF21 on VSMCs proliferation and migration was associated with inhibition of FGFR1/Syk/NLRP3 inflammasome, resulting in the improvement of neointima hyperplasia in diabetic mice.