背景:有据可查的是,在各种动物模型和人类中,高盐(HS)饮食会增加全身和血管的氧化应激,导致血管反应性受损。本研究研究了基因型和HS饮食摄入量的相互作用以及氧化应激-抗氧化系统平衡对血压正常的Tff3-/-/C57BL/6N敲除小鼠及其野生型(WT)对照的颈动脉加压扩张(FID)的潜在影响。
方法:男性,将10周龄的转基因Tff3-/-/C57BL/6N(Tff3-/-)敲除小鼠和WT/C57BL/6N(WT)(亲本品系)健康小鼠分为LS(啮齿动物食物中0.4%NaCl)和HS(啮齿动物食物中4%NaCl喂养1周)组。此外,LS和HS组用溶解在饮用水中的1mmol/L的4-羟基-2,2,6,6-四甲基哌啶-1-氧基(TEMPOL)处理。用氯胺酮(100mg/kg)和咪达唑仑(5mg/kg)麻醉后,测量血压,分离颈动脉和主动脉,并收集血液样本。
结果:FID在WT_HS小鼠中降低,并在体内被超氧化物清除剂TEMPOL恢复。另一方面,Tff3-/-小鼠的减毒FID不受HS饮食或TEMPOL体内治疗的进一步影响。两种菌株的HS饮食均增加了血管超氧化物/活性氧水平,并通过TEMPOL恢复。HS上调WT_HS和Tff3-/-HS小鼠谷胱甘肽过氧化物酶1(GPx1)基因表达,而GPx活性仅在WT_HS组显著降低。各组之间的氧化应激(oxLDL和AOPP)和动脉血压的全身(血清)标志物相似。
结论:HS饮食会增加WT小鼠的血管氧化应激并损害血管舒张功能。Tff3基因缺陷减弱血管舒张本身,没有HS摄入的进一步影响。这可以归因于Tff3-/-/C57BL/6N小鼠中抗氧化酶GPx1的血管上调,从而保护免受氧化应激。
BACKGROUND: It is well documented that high-salt (HS) diet increases systemic and vascular oxidative stress in various animal models and in humans, leading to impairment of vascular reactivity. The present study examined the interaction of genotype and HS diet intake and the potential effects of oxidative stress - antioxidative system balance on the flow-induced dilation (FID) in pressurized carotid arteries of normotensive Tff3-/-/C57BL/6N knockout mice and their wild-type (WT) controls.
METHODS: Male, ten-week-old transgenic Tff3-/-/C57BL/6N (Tff3-/-) knockout mice and WT/C57BL/6N (WT) (parental strain) healthy mice were divided in LS (0.4% NaCl in rodent chow) and HS (4% NaCl in rodent chow fed for 1 week) groups. Additionally, LS and HS groups were treated with 1 mmol/L 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) dissolved in the drinking water. After anesthesia with ketamine chloride (100 mg/kg) and midazolam (5 mg/kg), blood pressure was measured, carotid arteries and aortas were isolated, and blood samples were collected.
RESULTS: FID was decreased in WT_HS mice and restored by superoxide scavenger TEMPOL in vivo. On the other hand, attenuated FID of Tff3-/- mice was not further affected by HS diet or TEMPOL in vivo treatment. Vascular superoxide/reactive oxygen species levels were increased with HS diet in both strains and restored by TEMPOL. HS upregulated glutathione peroxidase 1 (GPx1) gene expression in WT_HS and Tff3-/-_HS mice, while GPx activity was significantly decreased only in WT_HS group. Systemic (serum) markers of oxidative stress (oxLDL and AOPP) and arterial blood pressure were similar among groups.
CONCLUSIONS: HS diet increases vascular oxidative stress and impairs vasodilation in WT mice. Tff3 gene deficiency attenuates vasodilation per se, without further effects of HS intake. This can be attributed to vascular upregulation of antioxidative enzyme GPx1 in Tff3-/-/C57BL/6N mice conferring protection from oxidative stress.