Abstract
Uric acid (UA) accumulation triggers endothelial dysfunction, oxidative stress and inflammation. Histone deacetylase (HDAC) play a vital role in regulating the pathological processes of various diseases. However, the influence of HDAC inhibitor on UA-induced vascular endothelial cell injury (VECI) remains undefined. Hence, this study aimed to investigate the effect of HDACs inhibition on UA-induced vascular endothelial cell dysfunction and its detailed mechanism. UA was employed to induce human umbilical vein endothelial cell (HUVEC) injury. Meanwhile, potassium oxonate- and hypoxanthine-induced hyperuricemia mouse models were also constructed. A broad-spectrum HDAC inhibitor trichostatin A (TSA) or selective HDAC6 inhibitor Tubsastain A (TubA) was given to HUVECs or mice to determine whether HDACs can affect UA-induced VECI. Results showed pretreatment of HUVECs with TSA or HDAC6 knockdown attenuated UA-induced VECI and increased FGF21 expression and phosphorylation of AKT, eNOS and FoxO3a. These effects could be reversed by FGF21 knockdown. In vivo, both TSA and TubA reduced inflammation and tissue injury while increased FGF21 expression and phosphorylation of AKT, eNOS and FoxO3a in the aortic and renal tissues of hyperuricemia mice. Therefore, HDACs, especially HDAC6 inhibitor, alleviated UA-induced VECI through upregulating FGF21 expression and then activating PI3K/AKT pathway. This suggests that HDAC6 may serve as a novel therapeutic target for treating UA-induced endothelial dysfunction.
Published Version
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