Jiménez-Altayó Francesc, Onetti Yara, Heras Magda, Dantas Ana P, Vila Elisabet
Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Cerdanyola del Vallès, Spain.
Age (Dordr). 2013 Aug;35(4):1219-34. doi: 10.1007/s11357-012-9450-6. Epub 2012 Jul 10.
The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation.
在加速衰老的小鼠模型（SAM）中，研究了两个已知的心血管危险因素——衰老和高脂饮食对肠系膜动脉反应性的影响。给5月龄的SAM易感性（SAMP8）和抗性（SAMR1）雌性小鼠喂食西式高脂饮食（8周）。解剖肠系膜动脉，分别通过线肌描记法、免疫荧光、RT-qPCR、乙锭荧光法和铁-二甲苯酚橙法评估血管反应性、蛋白质和信使RNA表达、超氧阴离子（O₂⁻）和过氧化氢生成。对氯化钾的收缩反应和对乙酰胆碱的舒张反应不受衰老和饮食的影响。尽管在SAMR1和SAMP8中观察到对去甲肾上腺素的收缩反应相似，但加速衰老与内皮型一氧化氮合酶（eNOS）和神经元型一氧化氮合酶（nNOS）减少以及O₂⁻合成增加有关。衰老相关的改变至少部分地通过诱导型一氧化氮合酶（iNOS）衍生的一氧化氮的贡献以及超氧化物歧化酶1增强内源性抗氧化能力来维持血管收缩而得到补偿。给予高脂饮食在SAMR1和SAMP8的肠系膜动脉去甲肾上腺素收缩反应中引起了质的不同的改变。SAMR1显示收缩增加，部分原因是eNOS和nNOS产生的一氧化氮可用性降低以及O₂⁻生成增加。相比之下，SAMP8喂食高脂饮食导致收缩减少，至少部分原因是iNOS衍生的一氧化氮功能参与增加。总之，血管衰老早期阶段的衰老依赖性内在改变可能促进血管适应，并易引发对高脂摄入的进一步变化，这可能导致与衰老相关的心血管疾病进展，而年轻受试者缺乏这种适应能力。
