School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
Medical School, University of Western Australia, Perth, WA, Australia.
Eur J Nutr. 2023 Jun;62(4):1845-1857. doi: 10.1007/s00394-023-03127-7. Epub 2023 Feb 28.
Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE mouse model. However most patients do not present clinically until well after the disease is established. The aims of this study were to determine whether chronic dietary nitrate supplementation can prevent or reverse the progression of atherosclerosis after disease is already established, as well as to explore the underlying mechanism of these cardiovascular protective effects.
60 apoE mice were given a high fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis. The mice were then randomized to (i) control group (HFD + 1 mmol/kg/day NaCl), (ii) moderate-dose group (HFD +1 mmol/kg/day NaNO3), or (iii) high-dose group (HFD + 10 mmol/kg/day NaNO3) (20/group) for a further 12 weeks. A group of apoE mice (n = 20) consumed a normal laboratory chow diet for 24 weeks and were included as a reference group.
Long-term supplementation with high dose nitrate resulted in ~ 50% reduction in plaque lesion area. Collagen expression and smooth muscle accumulation were increased, and lipid deposition and macrophage accumulation were reduced within atherosclerotic plaques of mice supplemented with high dose nitrate. These changes were associated with an increase in nitrite reductase as well as activation of the endogenous eNOS-NO pathway.
Long-term high dose nitrate significantly attenuated the progression of established atherosclerosis in the apoE mice fed a HFD. This appears to be mediated in part through a XOR-dependent reduction of nitrate to NO, as well as enhanced eNOS activation via increased Akt and eNOS phosphorylation.
动脉粥样硬化与内源性一氧化氮（NO）的生物利用度和/或生物活性降低有关。当内源性 NO 产生减少时，膳食硝酸盐已被提议作为替代来源。我们之前的研究表明，膳食硝酸盐对 apoE 小鼠模型中动脉粥样硬化的发展具有保护作用。然而，大多数患者直到疾病已经确立后才会出现临床症状。本研究旨在确定慢性膳食硝酸盐补充是否可以预防或逆转疾病已经确立后的动脉粥样硬化进展，并探讨这些心血管保护作用的潜在机制。
60 只 apoE 小鼠给予高脂肪饮食（HFD）12 周，以允许动脉粥样硬化的发生。然后，将这些小鼠随机分为（i）对照组（HFD+1mmol/kg/天 NaCl）、（ii）中剂量组（HFD+1mmol/kg/天 NaNO3）或（iii）高剂量组（HFD+10mmol/kg/天 NaNO3）（每组 20 只），进一步补充 12 周。一组 apoE 小鼠（n=20）摄入正常实验室饲料 24 周，并作为参考组纳入。
长期补充高剂量硝酸盐可使斑块病变面积减少约 50%。补充高剂量硝酸盐的小鼠的动脉粥样硬化斑块中的胶原表达和平滑肌积累增加，脂质沉积和巨噬细胞积累减少。这些变化与硝酸盐还原酶的增加以及内源性 eNOS-NO 途径的激活有关。
长期高剂量硝酸盐可显著减轻 HFD 喂养的 apoE 小鼠中已确立的动脉粥样硬化的进展。这似乎部分通过 XOR 依赖性将硝酸盐还原为 NO 以及通过增加 Akt 和 eNOS 磷酸化来增强 eNOS 激活来介导。
