Genotoxic Stress As a Trigger of Endothelial Dysfunction in Wistar Rats: a Molecular Genetic Study

IF 0.6 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Evolutionary Biochemistry and Physiology Pub Date : 2024-04-26 DOI:10.1134/s002209302402025x

M. Yu. Sinitsky, A. V. Sinitskaya, M. V. Khutornaya, M. A. Asanov, D. K. Shishkova, A. O. Poddubnyak, A. V. Ponasenko

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Abstract

Atherosclerosis and coronary artery disease are the leading causes of disability and mortality among the population. Genotoxic stress can be potentially considered as a new trigger of endothelial dysfunction underlying the pathogenesis of these diseases. This research was aimed to the study of molecular and genetic markers of genotoxic stress-induced endothelial dysfunction in normolipidemic Wistar rats. The study was carried out on male Wistar rats injected intravenously (tail vein) with the alkylating mutagen mitomycin C (MMC) at a dose of 0.5 mg/kg body weight (experimental group) or 0.9% NaCl solution (control group) three times a week for a month. Genotoxic stress in animals was assessed using a micronucleus assay in polychromatophilic erythrocytes (PCE); endothelial dysfunction was identified by assessing the expression of Vcam1, Icam1, Sele, Selp, Il6, Ccl2, Cxcl1, Mif, Vwf, Serpine1, Plau, Plat, Klf2, Klf4, Nfe2l2, Nos3, Snai1, Snai2, Twist1, Zeb1, Cdh5, and Cdh2 genes in the endothelial monolayer of the descending aorta. Rats of the experimental group developed pronounced genotoxic stress, as evidenced by a more than threefold increase in the frequency of micronucleated PCE and a decreased proportion of PCE in the total pool of erythrocytes analyzed. Gene expression profiling showed that rats of the experimental group exhibited a pro-inflammatory activation of the endothelium, accompanied by increased expression of Vcam1, Icam1, Selp, Il6, Ccl2 and Cxcl1 genes, as well as impaired endothelial mechanotransduction characterized by decreased expression of Klf2 and Klf4 genes. Thus, MMC-induced genotoxic stress in normolipidemic Wistar rats is associated with the two key pathogenic links of endothelial dysfunction and can be considered as one of its triggers.

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诱发 Wistar 大鼠内皮功能障碍的基因毒性应激：一项分子遗传学研究

摘要动脉粥样硬化和冠状动脉疾病是导致人口残疾和死亡的主要原因。基因毒性应激有可能被视为这些疾病发病机制中内皮功能障碍的新诱因。本研究旨在对正常血脂的 Wistar 大鼠基因毒性应激诱导的内皮功能障碍的分子和遗传标记进行研究。研究对象是雄性 Wistar 大鼠，通过尾静脉注射烷基化诱变剂丝裂霉素 C（MMC），剂量为 0.5 毫克/千克体重（实验组）或 0.9%氯化钠溶液（对照组），每周三次，持续一个月。用微核试验检测多嗜铬红细胞（PCE），评估动物的基因毒性应激反应；通过评估降主动脉内皮单层中 Vcam1、Icam1、Sele、Selp、Il6、Ccl2、Cxcl1、Mif、Vwf、Serpine1、Plau、Plat、Klf2、Klf4、Nfe2l2、Nos3、Snai1、Snai2、Twist1、Zeb1、Cdh5 和 Cdh2 基因的表达，确定内皮功能障碍。实验组大鼠出现了明显的基因毒性应激反应，表现为微核 PCE 的频率增加了三倍多，而且在分析的红细胞总数中 PCE 的比例下降。基因表达谱分析显示，实验组大鼠的内皮出现促炎性活化，Vcam1、Icam1、Selp、Il6、Ccl2 和 Cxcl1 基因表达增加，内皮的机械传导功能受损，Klf2 和 Klf4 基因表达减少。因此，在血脂正常的 Wistar 大鼠中，MMC 诱导的基因毒性应激与内皮功能障碍的两个关键致病环节有关，可被视为内皮功能障碍的诱因之一。

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来源期刊

Journal of Evolutionary Biochemistry and Physiology 生物-进化生物学

自引率

33.30%

发文量

110

审稿时长

6-12 weeks

期刊介绍： Journal of Evolutionary Biochemistry and Physiology publishes original experimental and theoretical and review articles related to evolution of the main forms of metabolism in connection with life origin; comparative and ontogenetic physiology and biochemistry, biochemical evolution of animal world; as well as evolution of functions; morphology, pharmacology, pathophysiology and ecological physiology. The journal welcomes manuscripts from all countries in the English or Russian language.