Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentaries

New Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization

  1. Guanghong Jia1,2 and
  2. James R. Sowers1,2,3,4⇑
  1. 1Division of Endocrinology, Diabetes and Metabolism and the Diabetes Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO
  2. 2Harry S. Truman Memorial Veterans' Hospital, Columbia, MO
  3. 3Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO
  4. 4Department of Internal Medicine, University of Missouri, Columbia, MO
  1. Corresponding author: James R. Sowers, sowersj{at}health.missouri.edu.
Diabetes 2014 Jan; 63(1): 39-41. https://doi.org/10.2337/db13-1530
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

By 2030, it is estimated that there will be 439 million people in the world with diabetes. Diabetes is a major risk factor for the development of atherosclerotic peripheral arterial disease (PAD), which is typically caused by progressive narrowing of the arteries in the lower extremities (1). Traditionally, the treatment of PAD has focused on smoking cessation, exercise to promote collateral blood flow, and pharmaceutical vasodilatation to optimize microvascular reserve. Often, aggressive revascularization such as angioplasty and bypass grafting is required to salvage limbs and avoid major amputation in patients with critical limb ischemia. However, restenosis rates after endovascular intervention are high, and while recent advances in drug-eluting balloons and stents have promise, their impact on limb salvage remains unproven (2). Recently, therapeutic angiogenesis has been proposed to induce new blood vessel growth for the treatment or prevention of critical limb ischemia by pharmacological and molecular targeting with vascular endothelial growth factor (VEGF), fibroblastic growth factor, granulocyte colony–stimulating factors, granulocyte-macrophage colony–stimulating factors, angiogenic gene therapy, and endothelial progenitor cells (3). Although preclinical and early-stage clinical results are promising, the strategy of augmenting expression of a single factor has failed to deliver significant clinical improvement. Thus, there remains a clear need for better interventions to induce therapeutic angiogenesis in diabetes-related PAD.

One therapeutic strategy is to increase nitric oxide (NO) in order to stimulate angiogenesis in conditions such as ischemia–reperfusion injury, cerebral ischemia, kidney injury, coronary artery disease, and PAD (4). NO induces endothelial cell (EC) migration, proliferation, angiogenesis, and VEGF expression, which, in turn, can further increase NO by enhancing endothelial NO synthase (eNOS) activity (Fig. 1). Multiple signaling pathways within ECs may be affected in response to NO generation, including cyclic guanosine monophosphate/protein kinase G, mitogen-activated protein kinases, hypoxia-inducible factor 1, and heme oxygenase 1 (5,6). Therapeutic strategies to increase NO are limited by the fact that NO is an unstable gaseous molecule and often metabolized before it reaches target cells. Pharmacological treatment with nitrite, an oxidation product of NO, may offer an alternative therapeutic approach since nitrite is considered to be highly stable, but nitrite has limited intrinsic biological activity at physiological ranges of pH and oxygen tension (7). Very important, conditions such as tissue chronic ischemia or ischemia reperfusion are optimal for the reduction of nitrite to NO by hypoxia, low pH, deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase (XOR), as well as aldehyde oxidase (8–10). Thus, nitrite reduction to NO may serve as a critical mechanism to maintain NO reservoirs during pathophysiological states to minimize tissue ischemia, dysfunction, and injury in cardiovascular diseases (Fig. 1).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Mechanisms of action for the NO2− in cardiovascular diseases. Under normal conditions, NO2− is fairly stable and available from conventional L-arginine/NOS pathway, NO2− therapy, and dietary consumption of NO3−/NO2− leading to salivary NO3− secretion and reduction to NO2− by commensal bacteria. However, during ischemia, low pH, and hypoxia, NO2− is reduced to NO via deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase, myoglobin, and aldehyde oxidase. NO induces EC migration, proliferation, and angiogenesis by activating cGMP/PKG, Ras-Raf, and MAPK signaling pathways. NO activates HIF-1 and heme oxygenase 1 pathways to increase VEGF production, which can increase NO in turn by upregulating eNOS activity. NO2− therapy confers substantial benefit to cardiovascular disease. cGMP, cyclic guanosine monophosphate; HIF-1, hypoxia-inducible factor 1; MAPK, mitogen-activated protein kinases; NO3−, nitrate; NO2−, nitrite; PKG, protein kinase G; RBC, red blood cell; ROS, reactive oxygen species; sGC, solube guanylate cyclase.

In this issue, Bir et al. (11) investigated the therapeutic effect of sodium nitrite treatment on the ischemic revascularization by using permanent unilateral femoral artery ligation in a diabetic mice model. This study convincingly demonstrates that nitrite administered intraperitoneally, restored ischemic hind limb blood flow, decreased oxidative stress, and stimulated EC proliferation, migration, and angiogenesis with a NO/VEGF-dependent manner in aged diabetic mice. Administration of nitrite resulted in increased tissue nitrite bioavailability, as well as increased levels of S-nitrosothiol and S-nitrosoheme in the ischemic hind limb. Furthermore, the proangiogenic actions of sodium nitrite were abrogated when febuxostat, an XOR inhibitor, was administered and therefore provided evidence that these effects were reliant on XOR activity. This study further confirms the findings of these investigators in a previous study, which indicated that the nitrite anion acts as a novel prodrug, undergoing one electron reduction back to NO under tissue ischemia in normal mice (12) (Fig. 1).

Overall, the data are interesting and potentially translational, with some important caveats. First, nitrite is reduced to NO only under special conditions such as ischemia, hypoxia, and low pH. In this regard, Bir et al. did not compare the difference of NO, VEGF, EC, and angiogenesis in normal and ischemic hind limbs within the same diabetic mouse model. This approach would be necessary to address the concern as to whether nitrite is a highly selective therapy agent only in local ischemic revascularization without undesired consequences, such as hypotension, retinopathy, methemoglobinemia, and potential tumor angiogenesis. Second, nitrite and nitrate can be applied in different clinical situations although there were negative results with nitrate therapy in this study. Further, there are translational limitations related to the intraperitoneal route of administration of nitrite in the current study. An oral formulation of sodium nitrite would be optimal for translational therapy in patients. In this regard, bioactivation of dietary nitrate is carried out mainly by commensal bacteria in the gastrointestinal tract that express effective nitrate reductase enzymes. Indeed, recent research in animals and humans has confirmed the beneficial effects of dietary nitrate in metabolic syndrome, hypertension, coronary heart disease, kidney injury, and pulmonary diseases (13,14). Third, while this study found that XOR was an important player in the reduction of nitrite to NO and augmented ischemic limb blood flow, it did not explore the role of other factors such as heme-containing protein and aldehyde oxidase involved in conversion of nitrite to NO. Further, hyperuricemia is more common in obese, diabetic, hypertensive, and elderly patients (15) and the use of an XOR in these patients may alter the impact of therapy with sodium nitrite in diabetic patients with PAD.

Despite the noted limitations, Bir et al. (11) provide strong support for the notion that nitrite therapy effectively enhances beneficial ischemic tissue vascular remodeling in the setting of diabetes and aging. A well-controlled and well-designed clinical trial is needed to elucidate whether nitrite therapy could be as effective in patients with diabetes and PAD.

Article Information

Acknowledgments. The authors would like to thank Brenda Hunter for her editorial assistance.

Funding. J.R.S. has received funding from the National Institutes of Health (R01-HL-73101-01A and R01-HL-107910-01) and the Veterans Affairs Merit System (0018).

Duality of Interest. No potential conflicts of interest relevant to this article were report.

Footnotes

  • See accompanying original article, p. 270.

  • © 2014 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

  1. ↵
    1. Albayati MA,
    2. Shearman CP
    . Peripheral arterial disease and bypass surgery in the diabetic lower limb. Med Clin North Am 2013;97:821–834pmid:23992894
    OpenUrlCrossRefPubMed
  2. ↵
    1. Conte MS
    . Diabetic revascularization: endovascular versus open bypass—do we have the answer? Semin Vasc Surg 2012;25:108–114pmid:22817861
    OpenUrlCrossRefPubMed
  3. ↵
    1. Raval Z,
    2. Losordo DW
    . Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res 2013;112:1288–1302pmid:23620237
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Kevil CG,
    2. Kolluru GK,
    3. Pattillo CB,
    4. Giordano T
    . Inorganic nitrite therapy: historical perspective and future directions. Free Radic Biol Med 2011;51:576–593pmid:21619929
    OpenUrlCrossRefPubMed
  5. ↵
    1. Kolluru GK,
    2. Shen X,
    3. Kevil CG
    . A tale of two gases: NO and H2S, foes or friends for life? Redox Biol 2013;1:313–318pmid:24024166
    OpenUrlCrossRefPubMed
  6. ↵
    1. Dulak J,
    2. Józkowicz A
    . Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies. Antioxid Redox Signal 2003;5:123–132pmid:12626124
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Calvert JW,
    2. Lefer DJ
    . Myocardial protection by nitrite. Cardiovasc Res 2009;83:195–203pmid:19251721
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Shiva S,
    2. Rassaf T,
    3. Patel RP,
    4. Gladwin MT
    . The detection of the nitrite reductase and NO-generating properties of haemoglobin by mitochondrial inhibition. Cardiovasc Res 2011;89:566–573pmid:20952414
    OpenUrlAbstract/FREE Full Text
    1. Cantu-Medellin N,
    2. Kelley EE
    . Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: Insights regarding where, when and how. Nitric Oxide 2013;34:19–26pmid:23454592
    OpenUrlCrossRefPubMed
  9. ↵
    1. Pinder AG,
    2. Pittaway E,
    3. Morris K,
    4. James PE
    . Nitrite directly vasodilates hypoxic vasculature via nitric oxide-dependent and -independent pathways. Br J Pharmacol 2009;157:1523–1530pmid:19594749
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    Bir SC, Pattillo CB, Pardue S, et al. Nitrite anion therapy protects against chronic ischemic tissue injury in db/db diabetic mice in a NO/VEGF-dependent manner. Diabetes 2014;63:270–281
  11. ↵
    1. Kumar D,
    2. Branch BG,
    3. Pattillo CB,
    4. et al
    . Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. Proc Natl Acad Sci USA 2008;105:7540–7545pmid:18508974
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Hendgen-Cotta UB,
    2. Luedike P,
    3. Totzeck M,
    4. et al
    . Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation 2012;126:1983–1992pmid:22992322
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Carlström M,
    2. Larsen FJ,
    3. Nyström T,
    4. et al
    . Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA 2010;107:17716–17720pmid:20876122
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Sowers JR
    . Diabetes mellitus and vascular disease. Hypertension 2013;61:943–947pmid:23595139
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Diabetes: 63 (1)

In this Issue

January 2014, 63(1)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
New Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
New Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization
Guanghong Jia, James R. Sowers
Diabetes Jan 2014, 63 (1) 39-41; DOI: 10.2337/db13-1530

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

New Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization
Guanghong Jia, James R. Sowers
Diabetes Jan 2014, 63 (1) 39-41; DOI: 10.2337/db13-1530
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
  • Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
  • Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
Show more Commentaries

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.