| [Objective] Exogenous chemicals which can cause changes in cellular genetic materials at chromosomal, molecular or basal level are known as DNA-damage agents (also called genotoxins). Most studies on DNA-damage agents focus on their potential danger as carcinogens, environmental risk assessment, and chemotherapeutic drug development. With the changes in the spectrum of human diseases in recent decades, the incidence of chronic non-communicable diseases is increasing year by year. Cardiovascular disease is especially harmful to humans. Preliminary results indicate that some DNA-damage agents may be closely related to the development of atherosclerosis and other cardiovascular diseases, but the relevant pathogenic mechanisms are not clear. Therefore, we chose three different DNA-damage agents:cisplatin, benzo(a)pyrene (BaP), and methyl methanesulfonate (MMS), to study their effects on contractile functon of toracic aorta in SD rats, and the underlying mechanisms.[Methods] We analyzed the effects of the three DNA-damage agents on contractile function of thoracic aorta by ex vivo perfusion system; and observed the ultrastructural changes of aortic wall by electral microscopy. MTT test was used to detected cell viability of vascular smooth muscle cells of SD rats (A7r5 cells); intracellular calcium ([Ca+]i) was measured by fluorescent dye labeling; Platelet aggregation was detected by platelet aggregation analyzer.[Results]1. Effect of cisplatin on contractile function of thoracic aorta in SD rats:1) Cisplatin did not directly affect vascular tone, but significantly reduced KCl and PE induced vascular contraction.2) Cisplatin damaged thoracic aorta wall structure, resulting in thinner smooth muscle layer, decreased smooth muscle cell count and damaged organelles (mitochondria and sarcoplasmic reticulum).3) Cisplatin significantly decreased survival rate of A7r5 cells in a dose-dependent manner, and this cytotoxicity is not reversible.4) Cisplatin significantly reduced ATP-induced [Ca2+]i increase in Human Umbilical Vein Endothelial Cells (HUVECs).2. Effect of BaP on contractile function of thoracic aorta in SD rats:1) BaP did not directly affect vascular tone, nor affected KCl and PE induced vascular contraction.2) BaP did not affect ATP-induced [Ca2+]i increase in HUVECs.3) KCl and PE induced contraction of rat thoracic aorta was significantly decreased in BaP-treated rat model, and ACh-induced endothelium-dependent vasodilation was also significantly reduced.4) After 4 weeks of BaP treatment, a slight decline in body weight of rats was observed, as well as increased blood pressure, while heart rate and peripheral inflammatory cell count remained unchanged.3. Effect of MMS on contractile function of thoracic aorta and platelet aggregation in SD rats:1) MMS did not affect the tension of rat thoracic aorta in in vivo and in vitro experiments.2) Exposure to MMS for 1 day caused significant decrease in body weight increase, and this trend remained after 3 days exposure.3) 1 day or 3 days after MMS treatment, no changes in heart rate and blood pressure were observed, and red blood cells and platelets remained normal. In contrary, number of peripheral inflammatory cells was significantly reduced.4) MMS exposure did not affect blood platelet aggregation in rats.[Conclusions]1. Cisplatin can directly affect contractile function of thoracic aorta in vitro, and this effect might be contributed to the damage of vascular wall and vascular smooth muscle cells, as well as decreased [Ca2+]i.2. Indirect-acting genotoxin BaP had to be metabolicaly activated before it exerting effect on the function of thoracic aortas.3. MMS does not affect the function of cardiovascular system. However, it significantly dicreased luekocyte counts, which may be related to its cytotoxicity to blood cells.4. Different types of DNA-damage agents had different effects on the contractile function of rat thoracic aorta, which may be related to their different mode of action.
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