Guizoni Daniele M, Dorighello Gabriel G, Oliveira Helena C F, Delbin Maria A, Krieger Marta H, Davel Ana P
Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, P.O. Box 6109, Campinas, São Paulo, Brazil.
J Transl Med. 2016 Jul 19;14(1):213. doi: 10.1186/s12967-016-0972-z.
Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr(-/-)), a genetic model of familial hypercholesterolemia.
Twelve-week-old C57BL/6J (WT) and LDLr(-/-) mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 × per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined.
Total cholesterol and triglycerides were increased in sedentary and exercised LDLr(-/-) mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr(-/-) mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr(-/-) mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr(-/-) mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr(-/-) mice. Furthermore, the aortas of sedentary LDLr(-/-) mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr(-/-) mice.
The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.
与高胆固醇血症相关的内皮功能障碍是动脉粥样硬化的早期事件，其特征是氧化还原失衡，伴有超氧化物产生增加以及一氧化氮（NO）和过氧化氢（H₂O₂）产生减少。有氧运动训练（AET）已被证明可改善晚期动脉粥样硬化中的动脉粥样硬化病变和氧化应激。然而，AET是否能预防家族性高胆固醇血症中内皮功能障碍的早期机制仍不清楚。本研究调查了AET对低密度脂蛋白受体敲除小鼠（LDLr⁻/⁻）主动脉内皮功能障碍和血管氧化还原状态的影响，LDLr⁻/⁻是家族性高胆固醇血症的一种遗传模型。
将12周龄的C57BL/6J（野生型，WT）和LDLr⁻/⁻小鼠分为久坐组和运动组（在跑步机上每周运动5次，每次1小时），持续4周。检测血脂谱、内皮功能以及主动脉中NO、H₂O₂和超氧化物产生的变化。
久坐和运动的LDLr⁻/⁻小鼠的总胆固醇和甘油三酯均升高。久坐的LDLr⁻/⁻小鼠主动脉中乙酰胆碱诱导的内皮依赖性舒张受损，但运动组未受损。抑制NO合酶（NOS）活性或用过氧化氢酶分解H₂O₂消除了动物之间乙酰胆碱反应的差异。NO供体硝普钠或H₂O₂诱导的舒张反应未观察到变化。久坐的LDLr⁻/⁻小鼠主动脉中神经元型NOS表达和内皮型NOS磷酸化（Ser1177）以及NO和H₂O₂产生减少，AET可使其恢复。用阿朴吗啡孵育可增加久坐但未运动的LDLr⁻/⁻小鼠中乙酰胆碱诱导的舒张，表明NADPH氧化酶在AET后内皮依赖性舒张中的参与较小。与这些发现一致，与久坐的LDLr⁻/⁻小鼠相比，运动的LDLr⁻/⁻小鼠主动脉中Nox2表达和超氧化物产生减少。此外，久坐的LDLr⁻/⁻小鼠主动脉中超氧化物歧化酶（SOD）同工型的表达降低，且铜/锌依赖性SODs在乙酰胆碱诱导的内皮依赖性舒张中的参与较小，这些异常在运动的LDLr⁻/⁻小鼠中部分减轻。
本研究收集的数据表明，AET作为一种潜在的非药物治疗方法，可通过增加NO生物利用度和H₂O₂产生，预防家族性高胆固醇血症中非常早期的内皮功能障碍和氧化还原失衡。
