nach oben

Erschienen in:

28.03.2017 | Article

Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice

verfasst von: Mika Kina-Tanada, Mayuko Sakanashi, Akihide Tanimoto, Tadashi Kaname, Toshihiro Matsuzaki, Katsuhiko Noguchi, Taro Uchida, Junko Nakasone, Chisayo Kozuka, Masayoshi Ishida, Haruaki Kubota, Yuji Taira, Yuichi Totsuka, Shin-ichiro Kina, Hajime Sunakawa, Junichi Omura, Kimio Satoh, Hiroaki Shimokawa, Nobuyuki Yanagihara, Shiro Maeda, Yusuke Ohya, Masayuki Matsushita, Hiroaki Masuzaki, Akira Arasaki, Masato Tsutsui

Erschienen in: Diabetologia | Ausgabe 6/2017

Einloggen, um Zugang zu erhalten

Abstract

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.

Methods

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.

Results

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.

Nur mit Berechtigung zugänglich

Eckel R (2015) The Metabolic Syndrome. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscaldo J (eds) Harrison's Principles of Internal Medicine. Mc Graw Hill Education, New York, pp 2449–2454

Beltran-Sanchez H, Harhay MO, Harhay MM, McElligott S (2013) Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J Am Coll Cardiol 62:697–703CrossRefPubMedPubMedCentral

Alberti KG, Eckel RH, Grundy SM et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645CrossRefPubMed

Mottillo S, Filion KB, Genest J et al (2010) The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 56:1113–1132CrossRefPubMed

Chen J, Muntner P, Hamm LL et al (2004) The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 140:167–174CrossRefPubMed

Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D (2012) Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 35:2402–2411CrossRefPubMedPubMedCentral

Garg PK, Biggs ML, Carnethon M et al (2014) Metabolic syndrome and risk of incident peripheral artery disease: the cardiovascular health study. Hypertension 63:413–419CrossRefPubMed

Hamaguchi M, Kojima T, Takeda N et al (2005) The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 143:722–728CrossRefPubMed

Hanley AJ, Karter AJ, Williams K et al (2005) Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation 112:3713–3721CrossRefPubMed

10.

Ignarro LJ (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30:535–560CrossRefPubMed

11.

Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012CrossRefPubMed

12.

Murad F (2006) Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 355:2003–2011CrossRefPubMed

13.

Tsutsui M, Shimokawa H, Otsuji Y, Ueta Y, Sasaguri Y, Yanagihara N (2009) Nitric oxide synthases and cardiovascular diseases: insights from genetically modified mice. Circ J 73:986–993CrossRefPubMed

14.

Tsutsui M, Shimokawa H, Otsuji Y, Yanagihara N (2010) Pathophysiological relevance of NO signaling in the cardiovascular system: novel insight from mice lacking all NO synthases. Pharmacol Ther 128:499–508CrossRefPubMed

15.

Tsutsui M, Tanimoto A, Tamura M et al (2015) Significance of nitric oxide synthases: Lessons from triple nitric oxide synthases null mice. J Pharmacol Sci 127:42–52CrossRefPubMed

16.

Kevil CG, Lefer DJ (2011) Review focus on inorganic nitrite and nitrate in cardiovascular health and disease. Cardiovasc Res 89:489–491CrossRefPubMed

17.

Lundberg JO, Weitzberg E, Gladwin MT (2008) The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7:156–167CrossRefPubMed

18.

Omar SA, Webb AJ (2014) Nitrite reduction and cardiovascular protection. J Mol Cell Cardiol 73:57–69CrossRefPubMed

19.

Milkowski A, Garg HK, Coughlin JR, Bryan NS (2010) Nutritional epidemiology in the context of nitric oxide biology: a risk-benefit evaluation for dietary nitrite and nitrate. Nitric Oxide 22:110–119CrossRefPubMed

20.

Weitzberg E, Lundberg JO (2013) Novel aspects of dietary nitrate and human health. Annu Rev Nutr 33:129–159CrossRefPubMed

21.

Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ (2007) Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A 104:19144–19149CrossRefPubMedPubMedCentral

22.

Bryan NS, Calvert JW, Gundewar S, Lefer DJ (2008) Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med 45:468–474CrossRefPubMedPubMedCentral

23.

Zhan J, Nakao A, Sugimoto R et al (2009) Orally administered nitrite attenuates cardiac allograft rejection in rats. Surgery 146:155–165CrossRefPubMed

24.

Park JW, Piknova B, Huang PL, Noguchi CT, Schechter AN (2013) Effect of blood nitrite and nitrate levels on murine platelet function. PLoS One 8:e55699CrossRefPubMedPubMedCentral

25.

Usui S, Hara Y, Hosaki S, Okazaki M (2002) A new on-line dual enzymatic method for simultaneous quantification of cholesterol and triglycerides in lipoproteins by HPLC. J Lipid Res 43:805–814PubMed

26.

Uchida T, Furuno Y, Tanimoto A et al (2014) Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse. J Mol Cell Cardiol 77:29–41CrossRefPubMed

27.

Satoh K, Satoh T, Kikuchi N et al (2014) Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res 115:738–750CrossRefPubMed

28.

Kim SW, Suda W, Kim S et al (2013) Robustness of gut microbiota of healthy adults in response to probiotic intervention revealed by high-throughput pyrosequencing. DNA Res 20:241–253CrossRefPubMedPubMedCentral

29.

Qin N, Yang F, Li A et al (2014) Alterations of the human gut microbiome in liver cirrhosis. Nature 513:59–64CrossRefPubMed

30.

Lecomte V, Kaakoush NO, Maloney CA et al (2015) Changes in gut microbiota in rats fed a high fat diet correlate with obesity-associated metabolic parameters. PLoS One 10:e0126931CrossRefPubMedPubMedCentral

31.

Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102:11070–11075CrossRefPubMedPubMedCentral

32.

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031CrossRefPubMed

33.

Vrieze A, Van Nood E, Holleman F et al (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143:913–916.e917

34.

Everard A, Belzer C, Geurts L et al (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 110:9066–9071CrossRefPubMedPubMedCentral

35.

Shin NR, Lee JC, Lee HY et al (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–735CrossRefPubMed

36.

Gauffin Cano P, Santacruz A, Moya A, Sanz Y (2012) Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 7:e41079CrossRefPubMedPubMedCentral

37.

Morishita T, Tsutsui M, Shimokawa H et al (2005) Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci U S A 102:10616–10621CrossRefPubMedPubMedCentral

38.

Nakata S, Tsutsui M, Shimokawa H et al (2008) Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation 117:2211–2223CrossRefPubMed

39.

Hattori Y, Suzuki M, Hattori S, Kasai K (2003) Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 46:1543–1549CrossRefPubMed

40.

Koh EH, Kim M, Ranjan KC et al (2010) eNOS plays a major role in adiponectin synthesis in adipocytes. Am J Physiol Endocrinol Metab 298:E846–E853CrossRefPubMed

41.

Bouskila M, Pajvani UB, Scherer PE (2005) Adiponectin: a relevant player in PPARgamma-agonist-mediated improvements in hepatic insulin sensitivity? Int J Obes 29(Suppl 1):S17–S23CrossRef

42.

Daval M, Foufelle F, Ferre P (2006) Functions of AMP-activated protein kinase in adipose tissue. J Physiol 574:55–62CrossRefPubMedPubMedCentral

43.

Sniderman AD, Furberg CD, Keech A et al (2003) Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 361:777–780CrossRefPubMed

44.

Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J (2008) Evaluating the glucose tolerance test in mice. Am J Physiol Endocrinol Metab 295:E1323–E1332CrossRefPubMed

45.

Windelov JA, Pedersen J, Holst JJ (2016) Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice. Physiol Rep 4:e12824CrossRefPubMedPubMedCentral

46.

Duplain H, Burcelin R, Sartori C et al (2001) Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104:342–345CrossRefPubMed

47.

Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (2004) Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 24:29–33CrossRefPubMed

48.

Romeo GR, Lee J, Shoelson SE (2012) Metabolic syndrome, insulin resistance, and roles of inflammation - mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 32:1771–1776CrossRefPubMedPubMedCentral

49.

Ridaura VK, Faith JJ, Rey FE et al (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341:1241214CrossRefPubMed

Titel: Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice
verfasst von: Mika Kina-Tanada
Mayuko Sakanashi
Akihide Tanimoto
Tadashi Kaname
Toshihiro Matsuzaki
Katsuhiko Noguchi
Taro Uchida
Junko Nakasone
Chisayo Kozuka
Masayoshi Ishida
Haruaki Kubota
Yuji Taira
Yuichi Totsuka
Shin-ichiro Kina
Hajime Sunakawa
Junichi Omura
Kimio Satoh
Hiroaki Shimokawa
Nobuyuki Yanagihara
Shiro Maeda
Yusuke Ohya
Masayuki Matsushita
Hiroaki Masuzaki
Akira Arasaki
Masato Tsutsui
Publikationsdatum: 28.03.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 6/2017
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4259-6

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Battle of Experts: Sport vs. Spritze bei Adipositas und Typ-2-Diabetes

11.05.2024 DDG-Jahrestagung 2024 Kongressbericht

Im Battle of Experts traten zwei Experten auf dem Diabeteskongress gegeneinander an: Die eine vertrat die Auffassung „Sport statt Spritze“ bei Adipositas und Typ-2-Diabetes, der andere forderte „Spritze statt Sport!“ Am Ende waren sie sich aber einig: Die Kombination aus beidem erzielt die besten Ergebnisse.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Klimawandel und Gesundheit: Was Sie in der Hausarztpraxis wissen müssen und tun können

Springer Medizin

Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice