Influences of lysine ‐specific demethylase 1 inhibitors on NO synthase–Kruppel‐like factor pathways in human endothelial cells in vitro and zebrafish (Danio rerio) larvae in vivo

In this study, we compared the influences of ORY-1001 (an LSD1 inhibitor being advanced into clinical trials) and 199 (a novel LSD1 inhibitor recently developed by us) to human umbilical vein endothelial cells (HUVECs) in vitro and further verified the bioeffects of ORY-1001 to zebrafish (Danio rerio) larvae in vivo. The results showed that up to 10  μM ORY-1001 or 199 did not significantly affect the cellular viability of HUVECs but substantially reduced the release of inflammatory interleukin-8 (IL-8) and IL-6. The signaling molecule in vasculatures, NO, was also increased in HUVECs. As the mechanism, the protein levels of endothelial NO sy nthase (eNOS) or p-eNOS, and their regulators Kruppel-like factor 2 (KLF2) or KLF4, were also increased after drug treatment. In vivo, 24 h treatment with up to 100 nM ORY-1001 reduced blood speed without changing morphologies or locomotor activities in zebrafish larvae. ORY-1001 treatment reduc ed the expression ofil8 but promoted the expression ofklf2a andnos in the zebrafish model. These data show that LSD1 inhibitors were not toxic but capable to inhibit inflammatory responses and affect the function of blood vessels through the up-regulation of the NOS-KLF pathway.

Source: Journal of Applied Toxicology - July 6, 2023 Category: Toxicology Authors: Jialin Yuan, Ruiman Que, Weichao Zhao, Fengmei Song, Yi Cao, Bin Yu Tags: RESEARCH ARTICLE Source Type: research