Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden.
Free Radic Biol Med. 2019 Dec;145:342-348. doi: 10.1016/j.freeradbiomed.2019.10.003. Epub 2019 Oct 7.
Nitric oxide (NO) is a key signalling molecule in the regulation of cardiometabolic function and impaired bioactivity is considered to play an important role in the onset and progression of cardiovascular and metabolic disease. Research has revealed an alternative NO-generating pathway, independent of NO synthase (NOS), in which the inorganic anions nitrate (NO) and nitrite (NO) are serially reduced to form NO. This work specifically aimed at investigating the role of commensal bacteria in bioactivation of dietary nitrate and its protective effects in a model of cardiovascular and metabolic disease. In a two-hit model, germ-free and conventional male mice were fed a western diet and the NOS inhibitor l-NAME in combination with sodium nitrate (NaNO) or placebo (NaCl) in the drinking water. Cardiometabolic parameters including blood pressure, glucose tolerance and body composition were measured after six weeks treatment. Mice in both placebo groups showed increased body weight and fat mass, reduced lean mass, impaired glucose tolerance and elevated blood pressure. In conventional mice, nitrate treatment partly prevented the cardiometabolic disturbances induced by a western diet and l-NAME. In contrast, in germ-free mice nitrate had no such beneficial effects. In separate cardiovascular experiments, using conventional and germ-free animals, we assessed NO-like signalling downstream of nitrate by administration of sodium nitrite (NaNO) via gavage. In this acute experimental setting, nitrite lowered blood pressure to a similar degree in both groups. Likewise, isolated vessels from germ-free mice robustly dilated in response to the NO donor sodium nitroprusside. In conclusion, our findings demonstrate the obligatory role of host-microbiota in bioactivation of dietary nitrate, thus contributing to its favourable cardiometabolic effects.
一氧化氮（NO）是调节心脏代谢功能的关键信号分子，生物活性受损被认为在心血管和代谢疾病的发生和进展中起着重要作用。研究揭示了一种独立于一氧化氮合酶（NOS）的替代 NO 生成途径，其中无机阴离子硝酸盐（NO）和亚硝酸盐（NO）被连续还原形成 NO。这项工作专门旨在研究共生细菌在膳食硝酸盐生物活化中的作用及其在心血管和代谢疾病模型中的保护作用。在双打击模型中，无菌和常规雄性小鼠喂食西式饮食，并在饮用水中添加 NOS 抑制剂 l-NAME 与硝酸钠（NaNO）或安慰剂（NaCl）。六周治疗后测量心血管代谢参数，包括血压、葡萄糖耐量和身体成分。两组安慰剂组的小鼠体重和脂肪量增加，瘦体重减少，葡萄糖耐量受损，血压升高。在常规小鼠中，硝酸盐处理部分预防了西式饮食和 l-NAME 引起的心脏代谢紊乱。相比之下，在无菌小鼠中，硝酸盐没有这种有益作用。在单独的心血管实验中，使用常规和无菌动物，我们通过灌胃给予亚硝酸钠（NaNO）来评估硝酸盐下游的类似 NO 的信号。在这种急性实验设置中，亚硝酸盐使两组的血压降低到相似的程度。同样，来自无菌小鼠的分离血管对一氧化氮供体硝普钠的反应强烈扩张。总之，我们的发现表明宿主-微生物群在膳食硝酸盐的生物活化中起着必需的作用，从而有助于其有利的心脏代谢作用。
