Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
Diabetologia. 2017 Jun;60(6):1138-1151. doi: 10.1007/s00125-017-4259-6. Epub 2017 Mar 28.
AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice.
To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water.
Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota.
CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.
目的/假设：一氧化氮（NO）不仅可以通过一氧化氮合酶（NOS）从 L-精氨酸合成，还可以从其惰性代谢物亚硝酸盐和硝酸盐合成。绿叶蔬菜富含硝酸盐，但饮食中缺乏亚硝酸盐/硝酸盐是否会自发导致疾病仍有待阐明。在这项研究中，我们检验了我们的假设，即长期饮食中缺乏亚硝酸盐/硝酸盐会在小鼠中引发代谢综合征。
为此，我们制备了一种低亚硝酸盐/硝酸盐饮食（LND），由基于氨基酸的低亚硝酸盐/硝酸盐饲料组成，其中 L-精氨酸、脂肪、碳水化合物、蛋白质和能量的含量与常规饲料相同，并且可饮用超纯水。饲料和水中均无法检测到亚硝酸盐和硝酸盐。
与常规饮食（RD）相比，3 个月的 LND 对野生型 C57BL/6J 小鼠的食物和水摄入量没有影响。然而，与 RD 相比，3 个月的 LND 显著引起内脏脂肪堆积、血脂异常和葡萄糖不耐受。18 个月的 LND 显著引起体重增加、高血压、胰岛素抵抗和乙酰胆碱诱导的内皮依赖性松弛受损，而 22 个月的 LND 则主要因心血管疾病导致死亡，包括急性心肌梗死。这些异常通过同时给予硝酸钠得到逆转，并且与内皮型一氧化氮合酶下调、脂联素不足和肠道微生物群失调显著相关。
结论/解释：这些结果首次提供了证据，表明长期饮食中缺乏亚硝酸盐/硝酸盐会导致小鼠代谢综合征、内皮功能障碍和心血管死亡，表明外源性 NO 产生系统在代谢综合征及其血管并发症中的新发病机制作用。
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