依帕列净对氧化胆固醇损伤的血管内皮和平滑肌细胞模型中 DNA 氧化变化的保护作用。

The protective effects of empagliflozin on DNA oxidative changes in a model of vascular endothelial and smooth muscle cells damaged by oxidized cholesterol.

机构信息

Medical University of Lodz, Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue Immunopharmacology, Kniaziewicza 1/5, 91-347 Lodz, Poland.

出版信息

Biomed Pharmacother. 2024 Jan;170:116065. doi: 10.1016/j.biopha.2023.116065. Epub 2023 Dec 28.

DOI:10.1016/j.biopha.2023.116065

PMID:38154272

Abstract

BACKGROUND

Diabetes patients often suffer chronic vascular complications resulting from endothelial dysfunction, smooth muscle cell (SMC) proliferation, inflammation and disturbed oxidative balance. Empagliflozin is one of three approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes mellitus.

THE AIM OF THIS STUDY

was to determine the protective and repairing effect of EMPA in a model of vascular endothelial and SMC damage with 25-hydroxycholesterol (25-OHC).

METHODS

Human umbilical vascular endothelial cells (HUVECs) and SMCs were treated with compounds which induce DNA single-strand breaks (SSBs) and subjected to comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined by the fluorescence of a 6-carboxy-2',7'-dichlorodihydrofluoresce probe in diacetate (HDCFDA).

RESULTS

25-OHC-stimulated SMCs showed greater resistance to ROS generation and DNA damage compared to HUVECs. In both experimental models, EMPA treatment was associated with lower ROS production and DNA damage, including oxidative damage to purines and pyrimidines. This effect was not dose-dependent. EMPA was found to counteract this DNA damage by inhibiting ROS production.

CONCLUSIONS

It appears that the EMPA induced indirect repair of DNA by inhibiting ROS production.

摘要

背景

糖尿病患者常患有慢性血管并发症，这是由内皮功能障碍、平滑肌细胞（SMC）增殖、炎症和氧化平衡紊乱引起的。恩格列净是三种已批准的用于 2 型糖尿病的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂之一。

本研究的目的

是确定 EMPA 在 25-羟胆固醇（25-OHC）引起的血管内皮和 SMC 损伤模型中的保护和修复作用。

方法

用人脐带血管内皮细胞（HUVEC）和 SMC 处理诱导 DNA 单链断裂（SSBs）的化合物，并进行彗星试验。使用内切核酸酶 III（Nth）或人 8-氧鸟嘌呤 DNA 糖基化酶（hOOG1）检测氧化 DNA 损伤。通过二乙酸酯（HDCFDA）中 6-羧基-2'，7'-二氯二氢荧光探针的荧光测定活性氧（ROS）的形成。

结果

与 HUVEC 相比，25-OHC 刺激的 SMC 显示出更强的抵抗 ROS 生成和 DNA 损伤的能力。在这两种实验模型中，EMPA 治疗与较低的 ROS 生成和 DNA 损伤相关，包括嘌呤和嘧啶的氧化损伤。这种作用不是剂量依赖性的。发现 EMPA 通过抑制 ROS 生成来抵抗这种 DNA 损伤。