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

Author:

Yuan Jialin1,Que Ruiman2,Zhao Weichao1,Song Fengmei1,Cao Yi1ORCID,Yu Bin3

Affiliation:

1. Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School University of South China Hengyang China

2. Department of Pharmacy, The Third Xiangya Hospital Central South University Changsha China

3. School of Pharmaceutical Sciences Zhengzhou University Zhengzhou China

Abstract

AbstractLysine‐specific demethylase 1 (LSD1) inhibitors are being developed for cancer therapy, but their bioeffects on vasculatures are not clear. 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 synthase (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 reduced the expression of il8 but promoted the expression of klf2a and nos 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Toxicology

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