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

Atherosclerosis and coronary artery disease are the leadingcauses of disability and mortality among the population. Genotoxicstress can be potentially considered as a new trigger of endothelialdysfunction underlying the pathogenesis of these diseases. Thisresearch was aimed to the study of molecular and genetic markersof genotoxic stress-induced endothelial dysfunction in normolipidemicWistar rats. The study was carried out on male Wistar rats injectedintravenously (tail vein) with the alkylating mutagen mitomycinC (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 assayin polychromatophilic erythrocytes (PCE); endothelial dysfunctionwas 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 monolayerof the descending aorta. Rats of the experimental group developedpronounced genotoxic stress, as evidenced by a more than threefoldincrease in the frequency of micronucleated PCE and a decreasedproportion of PCE in the total pool of erythrocytes analyzed. Geneexpression profiling showed that rats of the experimental groupexhibited a pro-inflammatory activation of the endothelium, accompaniedby increased expression of Vcam1, Icam1, Selp, Il6, Ccl2 and Cxcl1 genes, as well as impairedendothelial mechanotransduction characterized by decreased expressionof Klf2 and Klf4 genes. Thus, MMC-induced genotoxicstress in normolipidemic Wistar rats is associated with the two keypathogenic links of endothelial dysfunction and can be consideredas one of its triggers.