线粒体ATP敏感性钾离子通道开放剂对冠心病大鼠血脂代谢和血管内皮损伤的影响及相关机制研究

Impact and Related Mechanism of Mitochondrial ATP-sensitive Potassium Channel Openers on Blood Lipid Metabolism and Vascular Endothelial Injury in Rats with Coronary Heart Disease

背景线粒体ATP敏感性钾离子通道开放剂是一类扩血管药物,临床常用于治疗心脑血管疾病,但其对冠心病患者血脂代谢的影响、对血管内皮损伤的保护作用及相关机制尚不完全明确。目的探讨线粒体ATP敏感性钾离子通道开放剂对冠心病大鼠血脂代谢和血管内皮损伤的影响及机制。方法2018年8月-2019年2月,将50只6周龄SD大鼠随机分为对照组、模型组、低剂量组、中剂量组、高剂量组,每组10只。除对照组外,其他组大鼠均喂养高脂饲料、腹腔注射垂体后叶素制备冠心病大鼠模型,低、中、高剂量组大鼠分别按照二氮嗪3、5、7 mg/kg进行灌胃治疗,对照组、模型组大鼠均给予相同体积0.9%氯化钠溶液;五组大鼠均连续给药14 d。比较五组大鼠治疗前后血脂指标〔包括总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)〕,治疗后眼球血OD340值及颈动脉血管内皮细胞成纤维细胞生长因子2(FGF-2)、血管内皮生长因子(VEGF)相对表达量。结果治疗前模型组及低、中、高剂量组大鼠TC、TG、LDL-C水平高于对照组(P<0.05);治疗前五组大鼠HDL-C水平比较,差异无统计学意义(P>0.05);治疗后模型组及低、中、高剂量组大鼠TC、TG、LDL-C水平高于对照组,低、中、高剂量组大鼠TC、TG、LDL-C水平低于模型组,中、高剂量组大鼠TC、TG、LDL-C水平低于低剂量组,高剂量组大鼠TC、TG、LDL-C水平低于中剂量组(P<0.05);治疗后五组大鼠HDL-C水平比较,差异无统计学意义(P>0.05)。治疗后模型组大鼠眼球血OD340值低于对照组,中、高剂量组大鼠眼球血OD340值高于对照组,低、中、高剂量组大鼠眼球血OD340值高于模型组(P<0.05)。治疗后模型组及低、中剂量组大鼠颈动脉血管内皮细胞FGF-2及VEGF相对表达量高于对照组,低、中、高剂量组大鼠颈动脉血管内皮细胞FGF-2及VEGF相对表达量低于模型组(P<0.05)。结论线粒体ATP敏感性钾离子通道开放剂可通过抑制羟甲基戊二酰辅酶A(HMG-CoA)还原酶活性而改善冠心病大鼠血脂代谢,并可通过下调颈动脉血管内皮细胞FGF-2及VEGF的表达量而减轻血管内皮损伤。

Background Mitochondrial ATP-sensitive potassium channel openers,as a kind of vasodilators,is commonly used in the clinical treatment of cardiovascular and cerebrovascular diseases,however its impact and related mechanism on blood lipid metabolism and vascular endothelial injury in patients with coronary heart disease are not yet clear.Objective To investigate the impact and related mechanism of mitochondrial ATP-sensitive potassium channel openers on blood lipid metabolism and vascular endothelial injury in rats with coronary heart disease.Methods From August 2018 to February 2019,a total of 506-week-old SD rats were randomly divided into control group,model group,low-dose group,medium-dose group and high-dose group,with 10 cases in each group.Rats in model group,low-dose group,medium-dose group and high-dose group were fed with high-fat diet and intraperitoneal injection of pituitrin to prepare the models of coronary heart disease,moreover rats in low-dose group,medium-dose group and high-dose group were given intragastric administration of low-dose(3 mg/kg),medium-dose(5 mg/kg)and high-dose(7 mg/kg)diazoxide for 14 days,respectively,while rats in control group and model group were given 0.9%sodium chloride solution with same volume for 14 days.The blood lipid parameters(including TC,TG,LDL-C,HDL-C)before and after treatment,eyeball blood OD340 value,relative expression quantity of FGF-2 and VEGF of carotid vascular endothelial cells after treatment were compared in the five groups.Results TC,TG and LDL-C in model group,low-dose group,medium-dose group and high-dose group were statistically significantly higher than those in control group before treatment(P<0.05);there was no statistically significant difference in HDL-C in the five groups before treatment(P>0.05);after treatment,TC,TG and LDL-C in model group,low-dose group,medium-dose group and high-dose group were statistically significantly higher than those in control group,TC,TG and LDL-C in low-dose group,medium-dose group and high-dose group were statistically significantly lower than those in model group,TC,TG and LDL-C in medium-dose group and high-dose group were statistically significantly lower than those in low-dose group,TC,TG and LDL-C in high-dose group were statistically significantly lower than those in medium-dose group(P<0.05);but there was no statistically significant difference in HDL-C in the five groups after treatment(P>0.05).After treatment,eyeball blood OD340 value in model group was statistically significantly lower than that in control group,eyeball blood OD340 value in medium-dose group and high-dose group was statistically significantly higher than that in model group,respectively,eyeball blood OD340 value in low-dose group,medium-dose group and high-dose group was statistically significantly higher than that in model group,respectively(P<0.05).After treatment,relative expression quantity of FGF-2 and VEGF of carotid vascular endothelial cells in model group,low-dose group and medium-dose group was statistically significantly higher than that in control group,respectively,meanwhile relative expression quantity of FGF-2 and VEGF of carotid vascular endothelial cells in low-dose group,medium-dose group and high-dose group was statistically significantly lower than that in model group,respectively(P<0.05).Conclusion Mitochondrial ATP-sensitive potassium channel openers can improve the blood lipid metabolism through inhibition of the reductase activity of HMG-CoA in rats with coronary heart disease,as well as reduce the vascular endothelial injury through down-regulating the expressions of FGF-2 and VEGF of carotid vascular endothelial cells.