Nrf2-ARE抗氧化通路及GSK-3β在冠状动脉粥样硬化性心脏病中的作用
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摘要
背景：目前研究发现氧化应激在冠心病的发生发展中起到了重要的作用，同时新观点认为冠心病心肌重构的过程中也存在着心肌细胞的分裂及增殖。如何有效的遏制氧化应激、调节心肌细胞的细胞周期变化是治疗冠心病的新思路。目前研究证实白藜芦醇及瑞舒伐他汀等药物对冠心病有确切的保护作用，同时在分子研究领域人们发现Nrf2-ARE抗氧化通路在抗氧化应激过程中起到了至关重要的作用。而GSK-3β是一种调节细胞周期的重要蛋白，它的活性可影响细胞分化、增殖、凋亡等多个环节。本实验通过给予ApoE-/-小鼠高脂饮食，再分别给予白藜芦醇、瑞舒伐他汀灌胃，对比观察标本心血管的损害，研究核因子相关因子2（Nrf2）、总糖原合成激酶3β（GSK-3β）、磷酸化的GSK-3β等蛋白变化，进一步明确Nrf2-ARE抗氧化通路及GSK-3β在冠状动脉粥样硬化性心脏病发生、发展中的作用。
目的：建立白藜芦醇及瑞舒伐他汀对冠状动脉粥样硬化性心脏病的保护模型，检测Nrf2及GSK-3β的活性，以明确Nrf2-ARE抗氧化通路及GSK-3β在冠状动脉粥样硬化性心脏病发生、发展中的作用。
方法：将30只雄性体成熟8周龄清洁级ApoE-/-小鼠随机分成3组（每组10只），分别为：高脂饮食同时给予生理盐水灌胃组(在论文中简称对照组)、高脂饮食同时规律给予白藜芦醇灌胃组（简称白藜芦醇组）、高脂饮食同时规律给予瑞舒伐他汀灌胃组（简称瑞舒伐他汀组），各组小鼠其它生活环境相同。约每7天测量各个小鼠的体重，13周后处死小鼠，对心脏组织做病理切片，显微镜观察冠状动脉粥样硬化斑块的形成、心肌重塑的发生，同时用Western blot方法分别半定量测量各组心肌标本Nrf2、总GSK-3β、磷酸化的GSK-3β。
结果：
(1)体重变化：与对照组相比，白藜芦醇组与瑞舒伐他汀组表现出明显的体重控制作用。
(2)病理切片示：白藜芦醇组、瑞舒伐他汀组主动脉粥样硬化程度及心肌细胞损伤程度均小于对照组。
(3)通过与内参GADPH对比分析，对照组、白藜芦醇组及瑞舒伐他汀组总的GSK-3β表达变化不大；而白藜芦醇组磷酸化的GSK-3β表达与对照组相比上调，瑞舒伐他汀组磷酸化的GSK-3β表达与对照组相比下调；白藜芦醇组、瑞舒伐他汀组Nrf2表达均高于对照组，白藜芦醇组及瑞舒伐他汀组无统计学差异（P>0.05）。
结论：
(1)证明高脂饮食是诱发冠心病的危险因素之一。
(2)白藜芦醇与瑞舒伐他汀均有抗动脉粥样硬化及心肌细胞保护作用。
(3)白藜芦醇与瑞舒伐他汀均可影响高脂饮食所导致小鼠体重变化。
(4)白藜芦醇及瑞舒伐他汀可能通过Nrf2途径发挥抗动脉粥样硬化及心肌细胞保护作用。
Background: Recent studies have suggested oxidative stress play a critical role in theinitiation and progression of coronary arterioscleotic heart disease. In the new views, thereare also myocardial cell division and proliferation in the process of coronary heart diseasemyocardial remodeling. How to effectively defend against oxidative stress and regulate cellcycle of myocardial cells are new ideas to treat coronary heart disease. Untill present,resveratrol and rosuvastatin are demonstrated with the exactly protective effects on coronaryarterioscleotic heart disease and in the field of molecular studies, it was found thatNrf2-ARE antioxidant pathway plays the crucial role in antioxidant stress. Glycogensynthase kinase3β(GSK-3β) is a regulator of cell cycle proteins, its activity can affectnumerous aspects of cell differentiation, proliferation, and apoptosis. In this study,apolipoprotein(ApoE) knockout mice fed a high-fat diet, then given by gastric lavage toresveratrol and rosuvastatin respectively. We observed comparatively the specimens ofcardiovascular damage and research the changes of Nrf2, total GSK-3β and phosphorylatedGSK-3β to further clarify the cardiovascular effects and molecular mechanisms ofresveratrol.
Objective: To establish the protection models of resveratrol and rosuvastatin tocoronary arterioscleotic heart disease, and detect the activity of nuclear factor-erythroid2-related factor-2(Nrf2) and glycogen synthase kinase3β(GSK-3β) as to clear the the effectsof Nrf2-ARE antioxidant pathway and GSK-3β in coronary arterioscleotic heart disease.
Methods: Thirty male apolipoprotein(ApoE) knockout mice of age8weeks wererandomly divided into three groups(n=10,for each), including high-fat diet control group,high-fat diet-received resveratrol groups and high-fat diet-received rosuvastatin groups.Other living environment of all groups was same. Mice of the three groups were measuredweight every7days and were sacrificed after13weeks. The pathological slides made bymice heart tissues were abserved the formation of atherosclerotic lesions and development ofcardiac remodeling. Western blotting assay was used to detect Nrf2, total GSK-3β andphosphorylated GSK-3β by microscopy. We selected glyceraldehyde-3-phosphatedehydrogenase(GAPDH) as internal reference when detect.
Results:
1)Weight change: in comparison to the high-fat diet control group, a significant weightcontrol effect was abserved in high-fat diet-received resveratrol groups and high-fatdiet-received rosuvastatin groups.2)The pathological slides reveal: degree of aortic sclerosisand myocardial cells injury in high-fat diet-received resveratrol groups and high-fatdiet-received rosuvastatin groups are less than in the high-fat diet control group.3) All theresults of western blot are adjusted by GADPH. Total GSK-3β in the three groups has nosignificant difference; the gene expression of phosphorylated GSK-3β in high-fatdiet-received resveratrol groups was enhanced,but in high-fat diet-received rosuvastatingroups was decreased;the gene expression of Nrf2in high-fat diet-received resveratrolgroups and in high-fat diet-received rosuvastatin groups were higher than in the controlgroup, while no significant differences in the levels of Nrf2in high-fat diet-receivedresveratrol groups and in high-fat diet-received rosuvastatin groups（P>0.05）.
Conclusion:
1)These results demonstrate that high-fat diet can act as one of risk factors for coronaryartery disease.2)Resveratrol and rosuvastatin have effects on anti-atherosclerosis andprotection of myocardial cells.3)Resveratrol and rosuvastatin can both regulate the increaseddegree of weight caused by high-fat diet.4)The effects on anti-atherosclerosis and protectionof myocardial cells of resveratrol and rosuvastatin are probably via Nrf2-ARE molecularpathway.
目的：建立白藜芦醇及瑞舒伐他汀对冠状动脉粥样硬化性心脏病的保护模型，检测Nrf2及GSK-3β的活性，以明确Nrf2-ARE抗氧化通路及GSK-3β在冠状动脉粥样硬化性心脏病发生、发展中的作用。
方法：将30只雄性体成熟8周龄清洁级ApoE-/-小鼠随机分成3组（每组10只），分别为：高脂饮食同时给予生理盐水灌胃组(在论文中简称对照组)、高脂饮食同时规律给予白藜芦醇灌胃组（简称白藜芦醇组）、高脂饮食同时规律给予瑞舒伐他汀灌胃组（简称瑞舒伐他汀组），各组小鼠其它生活环境相同。约每7天测量各个小鼠的体重，13周后处死小鼠，对心脏组织做病理切片，显微镜观察冠状动脉粥样硬化斑块的形成、心肌重塑的发生，同时用Western blot方法分别半定量测量各组心肌标本Nrf2、总GSK-3β、磷酸化的GSK-3β。
结果：
(1)体重变化：与对照组相比，白藜芦醇组与瑞舒伐他汀组表现出明显的体重控制作用。
(2)病理切片示：白藜芦醇组、瑞舒伐他汀组主动脉粥样硬化程度及心肌细胞损伤程度均小于对照组。
(3)通过与内参GADPH对比分析，对照组、白藜芦醇组及瑞舒伐他汀组总的GSK-3β表达变化不大；而白藜芦醇组磷酸化的GSK-3β表达与对照组相比上调，瑞舒伐他汀组磷酸化的GSK-3β表达与对照组相比下调；白藜芦醇组、瑞舒伐他汀组Nrf2表达均高于对照组，白藜芦醇组及瑞舒伐他汀组无统计学差异（P>0.05）。
结论：
(1)证明高脂饮食是诱发冠心病的危险因素之一。
(2)白藜芦醇与瑞舒伐他汀均有抗动脉粥样硬化及心肌细胞保护作用。
(3)白藜芦醇与瑞舒伐他汀均可影响高脂饮食所导致小鼠体重变化。
(4)白藜芦醇及瑞舒伐他汀可能通过Nrf2途径发挥抗动脉粥样硬化及心肌细胞保护作用。
Background: Recent studies have suggested oxidative stress play a critical role in theinitiation and progression of coronary arterioscleotic heart disease. In the new views, thereare also myocardial cell division and proliferation in the process of coronary heart diseasemyocardial remodeling. How to effectively defend against oxidative stress and regulate cellcycle of myocardial cells are new ideas to treat coronary heart disease. Untill present,resveratrol and rosuvastatin are demonstrated with the exactly protective effects on coronaryarterioscleotic heart disease and in the field of molecular studies, it was found thatNrf2-ARE antioxidant pathway plays the crucial role in antioxidant stress. Glycogensynthase kinase3β(GSK-3β) is a regulator of cell cycle proteins, its activity can affectnumerous aspects of cell differentiation, proliferation, and apoptosis. In this study,apolipoprotein(ApoE) knockout mice fed a high-fat diet, then given by gastric lavage toresveratrol and rosuvastatin respectively. We observed comparatively the specimens ofcardiovascular damage and research the changes of Nrf2, total GSK-3β and phosphorylatedGSK-3β to further clarify the cardiovascular effects and molecular mechanisms ofresveratrol.
Objective: To establish the protection models of resveratrol and rosuvastatin tocoronary arterioscleotic heart disease, and detect the activity of nuclear factor-erythroid2-related factor-2(Nrf2) and glycogen synthase kinase3β(GSK-3β) as to clear the the effectsof Nrf2-ARE antioxidant pathway and GSK-3β in coronary arterioscleotic heart disease.
Methods: Thirty male apolipoprotein(ApoE) knockout mice of age8weeks wererandomly divided into three groups(n=10,for each), including high-fat diet control group,high-fat diet-received resveratrol groups and high-fat diet-received rosuvastatin groups.Other living environment of all groups was same. Mice of the three groups were measuredweight every7days and were sacrificed after13weeks. The pathological slides made bymice heart tissues were abserved the formation of atherosclerotic lesions and development ofcardiac remodeling. Western blotting assay was used to detect Nrf2, total GSK-3β andphosphorylated GSK-3β by microscopy. We selected glyceraldehyde-3-phosphatedehydrogenase(GAPDH) as internal reference when detect.
Results:
1)Weight change: in comparison to the high-fat diet control group, a significant weightcontrol effect was abserved in high-fat diet-received resveratrol groups and high-fatdiet-received rosuvastatin groups.2)The pathological slides reveal: degree of aortic sclerosisand myocardial cells injury in high-fat diet-received resveratrol groups and high-fatdiet-received rosuvastatin groups are less than in the high-fat diet control group.3) All theresults of western blot are adjusted by GADPH. Total GSK-3β in the three groups has nosignificant difference; the gene expression of phosphorylated GSK-3β in high-fatdiet-received resveratrol groups was enhanced,but in high-fat diet-received rosuvastatingroups was decreased;the gene expression of Nrf2in high-fat diet-received resveratrolgroups and in high-fat diet-received rosuvastatin groups were higher than in the controlgroup, while no significant differences in the levels of Nrf2in high-fat diet-receivedresveratrol groups and in high-fat diet-received rosuvastatin groups（P>0.05）.
Conclusion:
1)These results demonstrate that high-fat diet can act as one of risk factors for coronaryartery disease.2)Resveratrol and rosuvastatin have effects on anti-atherosclerosis andprotection of myocardial cells.3)Resveratrol and rosuvastatin can both regulate the increaseddegree of weight caused by high-fat diet.4)The effects on anti-atherosclerosis and protectionof myocardial cells of resveratrol and rosuvastatin are probably via Nrf2-ARE molecularpathway.
引文
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