脂联素对高脂血症大鼠血管内皮功能的改善作用及其机制研究
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摘要
研究背景
随着社会的发展、居民生活水平的提高及生活方式的改变,由高脂血症引起的以肥胖、胰岛素抵抗、高血压为表现的代谢综合征(MS)的发病率逐年升高并呈年轻化趋势,由此导致的心血管疾病的发生已成为危害人类健康的主要杀手。大量的基础研究表明,血管内皮是许多心血管疾病或危险因子作用的重要靶器官,它具有相当活跃的内分泌和代谢功能;进一步的研究证实,由精氨酸缺乏、一氧化氮合酶(NOS)表达改变及超氧化物导致的一氧化氮(NO)破坏增加及其它多种因素参与的内皮功能紊乱,可使血管收缩与舒张因子、促凝血和抗凝血介质、促生长和抑制生长物质之间的平衡失调,从而构成了这些心血管疾病的共同病理生理基础。因此,寻求改善内皮功能的途径,能够为防治高脂血症与MS向心血管疾病发展提供新的思路及策略。
近年来,随着对脂肪组织生物学功能研究的深入,人们逐渐发现,脂肪组织产生的多种生物活性物质,不但对体内能量代谢有着重要调节作用,还可以调节心血管系统的结构与功能。因此脂肪组织已被公认为人体内最大的内分泌器官。在脂肪细胞分泌的众多生物活性物质中,脂联素(Adiponectin)是最新且生物活性最为重要的脂肪细胞因子,因而成为研究最为活跃的焦点。近年临床观察表明,血浆脂联素水平与内皮功能失调及冠心病的发病率呈显著负相关,提示脂联素可能是一种强有力的内皮保护因子。然而目前国内外对其机制的研究仍不完善,特别是对脂联素在高脂血症这一MS中至关重要的病变环节所致内皮功能失调中的作用目前知之甚少。因此阐明脂联素与高脂血症性内皮功能障碍的关系及其作用机理无疑对于揭示脂联素改善内皮功能的机理具有重要的理论意义,且对于将脂联素用于防治内皮功能障碍相关性疾病具有广阔的临床应用前景。
研究目的
1.明确脂联素对高脂血症所致内皮功能障碍的抑制作用。
2.阐明脂联素改善内皮功能的信号机制,尤其是脂联素与血管内源性NOS-NO系统及血管氧化应激之间的关系。
实验方法
选用成年SD大鼠,随机分为正常饮食组及高脂饮食组。14周后,取其主动脉,以脂联素球状片段gAd(2μg/ml)孵育4小时。观察gAd对血管内皮功能,NO、超氧化物及过氧化亚硝酸阴离子的生成,NADPH氧化酶的表达以及NOS的活性和表达的影响。
实验结果
1.脂联素可以增加高脂血症大鼠血管对内皮依赖性血管舒张剂的舒张反应,显著改善其血管内皮功能。
2.尽管脂联素能够改善高脂血症大鼠血管内皮功能,但未增加其血管NO的生成。进一步实验发现,它可促进内皮型NOS(eNOS)的活性及磷酸化表达,抑制诱导型NOS(iNOS)的活性及表达。
3.脂联素可抑制高脂血症大鼠血管超氧化物(·O2?)的生成和NADPH氧化酶的表达,同时促进其抗氧化物的活性。
4.脂联素能够降低高脂血症大鼠血管过氧化亚硝酸阴离子(ONOO?)的生成量。
结论
1.本研究首次发现,脂联素急性治疗可显著抑制高脂血症介导的血管内皮功能失调。
2.进一步研究表明,脂联素抑制超氧化物生成、保护生物活性NO、阻断毒性ONOO?形成,是其改善内皮功能,发挥血管保护作用的重要机制。
Background
Metabolic syndrome is characterized by a group of metabolic and hemostatic abnormalities, including impaired glucose tolerance, hyperinsulinemia, hypertension, dyslipidemia, oxidant stress, and endothelial dysfunction. Considerable evidence from both animal experiments and clinical observations indicates that endothelial dysfunction, which was involved in deficiencies of arginine supply, alterations of nitric oxide synthase (NOS) expression and increased destruction of nitric oxide (NO) by superoxide (·O2?), contributes significantly to subsequent development of cardiovascular disease through a variety of pathological pathways in metabolic syndrome. Therefore, improvement of endothelial dysfunction is an available approach that can reduce morbility and mortality of cardiovascular disease caused by metabolic syndrome.
Adiponectin is a novel cytokine secreted from adipose tissue. Clinical observations have demonstrated that hypoadiponectinemia is closely related to endothelial dysfunction in peripheral arteries and that plasma total adiponectin concentrations are inversely related to the risk of myocardial infarction. These results suggest that adiponectin might be a potent endothelial protective molecule. However, whether supplementation of adiponectin may attenuate endothelial dysfunction caused by hyperlipidemia has not been previously investigated. To determine whether adiponectin might improve endothelial function in hyperlipidemic animals and to investigate the mechanisms involved show a light on the possibility that therapeutic application of gAd may be a useful treatment of metabolic disorders with vascular complication.
Aims
1. To determine whether treatment with adiponectin might improve endothelial function in vascular segments isolated from hyperlipidemic animals.
2. If so, to investigate the mechanisms through which adiponectin exerts its vasculoprotective effects in hyperlipidemic rats, especially its actions associated with vascular NO bioactivity and oxidative stress. Methods
Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd, 2μg/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91phox expression, and endothelial/inducible nitric oxide synthase activity/ expression was determined.
Results
1. Treatment of hyperlipidemic aortic segments in vitro with gAd enhanced acetylcholine (ACh)-induced vasorelaxation in an NO-dependent fashion.
2. Treatment with gAd had no significant effect on hyperlipidemia-induced NO overproduction. Further study showed gAd enhanced eNOS phosphorylation and inhibited iNOS expression in hyperlipidemic vessels.
3. Treatment with gAd significantly reduced superoxide (·O2?) and NADPH oxidase (gp91phox) overexpression, meanwhile, enhanced antioxidant capacity in hyperlipidemic vessels.
4. Treatment with gAd attenuated peroxynitrite overproduction in hyperlipidemic vessels.
Conclusions
1. We have observed for the first time that acute treatment with gAd significantly attenuated hyperlipidemia induced endothelial dysfunction.
2. We have provided direct evidence that inhibiting superoxide production, preserving NO from destruction, and blocking the formation of toxic ONOO? are the major mechanisms by which adiponectin exerts its vasculoprotective effect.
随着社会的发展、居民生活水平的提高及生活方式的改变,由高脂血症引起的以肥胖、胰岛素抵抗、高血压为表现的代谢综合征(MS)的发病率逐年升高并呈年轻化趋势,由此导致的心血管疾病的发生已成为危害人类健康的主要杀手。大量的基础研究表明,血管内皮是许多心血管疾病或危险因子作用的重要靶器官,它具有相当活跃的内分泌和代谢功能;进一步的研究证实,由精氨酸缺乏、一氧化氮合酶(NOS)表达改变及超氧化物导致的一氧化氮(NO)破坏增加及其它多种因素参与的内皮功能紊乱,可使血管收缩与舒张因子、促凝血和抗凝血介质、促生长和抑制生长物质之间的平衡失调,从而构成了这些心血管疾病的共同病理生理基础。因此,寻求改善内皮功能的途径,能够为防治高脂血症与MS向心血管疾病发展提供新的思路及策略。
近年来,随着对脂肪组织生物学功能研究的深入,人们逐渐发现,脂肪组织产生的多种生物活性物质,不但对体内能量代谢有着重要调节作用,还可以调节心血管系统的结构与功能。因此脂肪组织已被公认为人体内最大的内分泌器官。在脂肪细胞分泌的众多生物活性物质中,脂联素(Adiponectin)是最新且生物活性最为重要的脂肪细胞因子,因而成为研究最为活跃的焦点。近年临床观察表明,血浆脂联素水平与内皮功能失调及冠心病的发病率呈显著负相关,提示脂联素可能是一种强有力的内皮保护因子。然而目前国内外对其机制的研究仍不完善,特别是对脂联素在高脂血症这一MS中至关重要的病变环节所致内皮功能失调中的作用目前知之甚少。因此阐明脂联素与高脂血症性内皮功能障碍的关系及其作用机理无疑对于揭示脂联素改善内皮功能的机理具有重要的理论意义,且对于将脂联素用于防治内皮功能障碍相关性疾病具有广阔的临床应用前景。
研究目的
1.明确脂联素对高脂血症所致内皮功能障碍的抑制作用。
2.阐明脂联素改善内皮功能的信号机制,尤其是脂联素与血管内源性NOS-NO系统及血管氧化应激之间的关系。
实验方法
选用成年SD大鼠,随机分为正常饮食组及高脂饮食组。14周后,取其主动脉,以脂联素球状片段gAd(2μg/ml)孵育4小时。观察gAd对血管内皮功能,NO、超氧化物及过氧化亚硝酸阴离子的生成,NADPH氧化酶的表达以及NOS的活性和表达的影响。
实验结果
1.脂联素可以增加高脂血症大鼠血管对内皮依赖性血管舒张剂的舒张反应,显著改善其血管内皮功能。
2.尽管脂联素能够改善高脂血症大鼠血管内皮功能,但未增加其血管NO的生成。进一步实验发现,它可促进内皮型NOS(eNOS)的活性及磷酸化表达,抑制诱导型NOS(iNOS)的活性及表达。
3.脂联素可抑制高脂血症大鼠血管超氧化物(·O2?)的生成和NADPH氧化酶的表达,同时促进其抗氧化物的活性。
4.脂联素能够降低高脂血症大鼠血管过氧化亚硝酸阴离子(ONOO?)的生成量。
结论
1.本研究首次发现,脂联素急性治疗可显著抑制高脂血症介导的血管内皮功能失调。
2.进一步研究表明,脂联素抑制超氧化物生成、保护生物活性NO、阻断毒性ONOO?形成,是其改善内皮功能,发挥血管保护作用的重要机制。
Background
Metabolic syndrome is characterized by a group of metabolic and hemostatic abnormalities, including impaired glucose tolerance, hyperinsulinemia, hypertension, dyslipidemia, oxidant stress, and endothelial dysfunction. Considerable evidence from both animal experiments and clinical observations indicates that endothelial dysfunction, which was involved in deficiencies of arginine supply, alterations of nitric oxide synthase (NOS) expression and increased destruction of nitric oxide (NO) by superoxide (·O2?), contributes significantly to subsequent development of cardiovascular disease through a variety of pathological pathways in metabolic syndrome. Therefore, improvement of endothelial dysfunction is an available approach that can reduce morbility and mortality of cardiovascular disease caused by metabolic syndrome.
Adiponectin is a novel cytokine secreted from adipose tissue. Clinical observations have demonstrated that hypoadiponectinemia is closely related to endothelial dysfunction in peripheral arteries and that plasma total adiponectin concentrations are inversely related to the risk of myocardial infarction. These results suggest that adiponectin might be a potent endothelial protective molecule. However, whether supplementation of adiponectin may attenuate endothelial dysfunction caused by hyperlipidemia has not been previously investigated. To determine whether adiponectin might improve endothelial function in hyperlipidemic animals and to investigate the mechanisms involved show a light on the possibility that therapeutic application of gAd may be a useful treatment of metabolic disorders with vascular complication.
Aims
1. To determine whether treatment with adiponectin might improve endothelial function in vascular segments isolated from hyperlipidemic animals.
2. If so, to investigate the mechanisms through which adiponectin exerts its vasculoprotective effects in hyperlipidemic rats, especially its actions associated with vascular NO bioactivity and oxidative stress. Methods
Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd, 2μg/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91phox expression, and endothelial/inducible nitric oxide synthase activity/ expression was determined.
Results
1. Treatment of hyperlipidemic aortic segments in vitro with gAd enhanced acetylcholine (ACh)-induced vasorelaxation in an NO-dependent fashion.
2. Treatment with gAd had no significant effect on hyperlipidemia-induced NO overproduction. Further study showed gAd enhanced eNOS phosphorylation and inhibited iNOS expression in hyperlipidemic vessels.
3. Treatment with gAd significantly reduced superoxide (·O2?) and NADPH oxidase (gp91phox) overexpression, meanwhile, enhanced antioxidant capacity in hyperlipidemic vessels.
4. Treatment with gAd attenuated peroxynitrite overproduction in hyperlipidemic vessels.
Conclusions
1. We have observed for the first time that acute treatment with gAd significantly attenuated hyperlipidemia induced endothelial dysfunction.
2. We have provided direct evidence that inhibiting superoxide production, preserving NO from destruction, and blocking the formation of toxic ONOO? are the major mechanisms by which adiponectin exerts its vasculoprotective effect.
引文
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