Dietary nitrate, nitric oxide, and restenosis
Open accessAbstract
Endothelium-derived NO controls the contractility and growth state of the underlying vascular smooth muscle cells and regulates the interaction of the vessel wall with circulating blood elements. Acute injury of the vessel wall denudes the endothelial lining, removing homeostatic regulation and precipitating a wave of events leading to myointimal hyperplasia. In this issue of the JCI, Alef and colleagues provide evidence that in the injured vessel wall, the disruption of the NOS pathway is countered by induction of xanthine oxidoreductase, an enzyme capable of producing NO from nitrite. In addition, they link low dietary nitrite levels to increased severity of myointimal hyperplasia following vessel injury in mice.
AI snapshot
Written from the paper’s full text.
TL;DR
This commentary discusses how dietary nitrite/nitrate can be converted to NO in the injured vessel wall, countering NOS dysfunction and limiting myointimal hyperplasia. It highlights Alef et al.’s findings that sodium nitrite reduces restenosis-like injury in animal models via xanthine oxidoreductase and warns that direct nitrite/nitrate supplementation needs more clinical evidence.
Key findings
- In the injured vessel wall, NOS pathway disruption is countered by induction of xanthine oxidoreductase (XOR), which can produce NO from nitrite.
- Sodium nitrite reduced myointimal hyperplasia after vascular injury by 50%–80%, depending on route of administration, and was associated with a 10-fold increase in NO generation by injured vessels; this effect was not attenuated by the NOS inhibitor L-NAME.
- XOR antagonism with allopurinol blocked the antiproliferative action of sodium nitrite in vitro and abrogated the therapeutic effect of dietary nitrite on injured murine carotid artery; reduced dietary nitrogen oxides aggravated myointimal hyperplasia, and dietary tungsten also increased its severity.
- The commentary notes potential harms of dietary nitrite/nitrate supplementation, including methemoglobinemia and formation of potentially carcinogenic nitrosamines, and states that direct supplementation seems inadvisable until larger randomized clinical trials provide more guidance.
Methods
- Design: narrative commentary/review on Alef et al. and the nitrate–nitrite–NO pathway, not a primary experimental study.
- Data discussed: rat carotid artery balloon angioplasty injury, cultured vascular smooth muscle cells, murine carotid artery injury, and dietary nitrite/nitrate manipulations.
- Analysis: synthesis of cited experimental findings and proposed mechanisms, including XOR-mediated nitrite reduction to NO.
Limitations
- The paper states that direct dietary supplementation with nitrite or nitrate salts may cause methemoglobinemia, interfere with blood oxygenation, and contribute to nitrosamine formation; it calls for larger randomized clinical trials before supplementation is advised.
- Evident from the text: this is a commentary without primary data, so its conclusions depend on the cited Alef et al. study and other referenced work.
- Evident from the provided text: it contains unrelated anaphylaxis passages, suggesting the file is composite or corrupted.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 40 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Low dietary nitrite levels are linked to increased severity of myointimal hyperplasia following vessel injury in mice.
“In addition, they link low dietary nitrite levels to increased severity of myointimal hyperplasia following vessel injury in mice.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Cardiovascular risk factors such as hypercholesterolemia and diabetes mellitus impair the synthesis and bioactivity of endothelium-derived NO.
“Cardiovascular risk factors (e.g., hypercholesterolemia, diabetes mellitus) impair the synthesis and bioactivity of endothelium-derived NO (4, 5).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
In the injured vessel wall, disruption of the NOS pathway is countered by induction of xanthine oxidoreductase, an enzyme capable of producing NO from nitrite.
“In this issue of the JCI, Alef and colleagues provide evidence that in the injured vessel wall, the disruption of the NOS pathway is countered by induction of xanthine oxidoreductase, an enzyme capable of producing NO from nitrite.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Rests on an assumption: XOR is an enzyme capable of producing NO from nitrite.
- Premisecitation
Endothelium-derived NO suppresses endothelial expression of adhesion molecules and chemokines that would otherwise initiate vascular inflammation.
“Finally, endotheliumderived NO suppresses the endothelial expression of adhesion molecules and chemokines that would otherwise initiate vascular inflammation (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
- Premisecitation
Vascular injury induced the expression of vascular iNOS.
“They also confirmed that vascular injury induced the expression of vascular iNOS.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
At the site of vascular injury, arginase is induced, converting arginine to urea and ornithine.
“At the site of vascular injury, arginase is induced, converting arginine to urea and ornithine (8).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] source
Not checked in the free run.
- Premisecitation
One week after vascular injury, arginase-1 expression and activity were increased in the injured vessel wall.
“One week after vascular injury, arginase-1 expression and activity were increased in the injured vessel wall.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premiseown data
The antiproliferative effect of sodium nitrite was associated with upregulation of p21 Wafl/Cip1, which is known to mediate in part the antiproliferative effect of NO.
“This effect was associated with upregulation of the cyclin-dependent kinase inhibitor p21 Wafl/Cip1 , which is known to mediate in part the antiproliferative effect of NO.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premiseown data
Sodium nitrite increased NO generated by cultured VSMCs in a NOS-independent manner.
“Sodium nitrite increased NO generated by cultured VSMCs, also in a NOS-independent manner.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Regression of established myointimal hyperplasia could be induced by supplemental sodium nitrite.
“In subsequent studies, they documented that regression of estab-lished myointimal hyperplasia could be induced by supplemental sodium nitrite.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Sodium nitrite reduced myointimal hyperplasia after vascular injury by 50%-80%, depending upon the route of administration.
“Sodium nitrite reduced myointimal hyperplasia after vascular injury by 50%-80%, depending upon the route of administration.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Interpretationreasoning
Dietary nitrite was converted to NO by XOR in the vessel wall.
“These studies suggest that dietary nitrite was converted to NO by XOR in the vessel wall.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Rests on an assumption: XOR is an enzyme capable of producing NO from nitrite.
- Premiseown data
Sodium nitrite inhibited proliferation of cultured VSMCs in vitro.
“Furthermore, sodium nitrite inhibited proliferation of the cells in vitro.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Vascular injury induced the expression and activity of XOR in the vessel wall.
“Alef et al. observed that vascular injury induced the expression and activity of XOR in the vessel wall.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Interpretationcitation
A similar process occurs in the vessel wall, where nitrite is also converted to NO.
“The current study indicates that a similar process occurs in the vessel wall, where NO 2 -is also converted to NO.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Interpretationcitation
The human nitrate cycle may account for some of the anti-hypertensive effect observed in diets enriched in vegetables and fruit, such as in the DASH study.
“This human nitrate cycle may account for some of the anti-hypertensive effect observed in diets that are enriched in vegetables and fruit, such as in the DASH (Dietary Approaches to Stop Hypertension) study (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Dykhuizen, 1997, N Engl J Med. source
Not checked in the free run.
- Premiseown data
A reduction in dietary nitrogen oxides aggravated myointimal hyperplasia after vascular injury.
“A dietary source of nitrite was important in this response, as a reduction in dietary nitrogen oxides aggravated the myointimal hyperplasia after vascular injury.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Dietary tungsten, which inhibits XOR, increased the severity of myointimal hyperplasia.
“Furthermore, dietary tungsten (which inhibits XOR) also increased the severity of myointimal hyperplasia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
- Premisecitation
Nitrous acid decomposes into nitrite, NO, and water.
“Subsequently, HNO 2 decomposes into NO 2 -, NO, and water.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- Premisecitation
Anaerobic bacteria in the mouth that express nitrate reductases convert nitrate to nitrite.
“Anaerobic bacteria in the mouth that express nitrate reductases subsequently convert the nitrate to nitrite.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- Premisecitation
When nitrite-rich saliva is swallowed, it reacts with acidic gastric juices to form nitrous acid, which is exceptionally active as an antibacterial.
“When nitrite-rich saliva is swallowed, it reacts with the acidic gastric juices to form nitrous acid (HNO 2 ), which is exceptionally active as an antibacterial.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- Premisecitation
The salivary glands extract nitrate from plasma, concentrating it 10- to 20-fold.
“The salivary glands extract NO 3 -from the plasma, concentrating it 10-to 20-fold (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- May combine two claims. 12
- Classified as probably not a substantial claim. 4
May combine two claims.
PremisecitationEndothelium-derived NO controls the contractility and growth state of the underlying vascular smooth muscle cells and regulates the interaction of the vessel wall with circulating blood elements.
“Endothelium-derived NO controls the contractility and growth state of the underlying vascular smooth muscle cells and regulates the interaction of the vessel wall with circulating blood elements.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNO activates soluble guanylate cyclase to produce cGMP, which participates in signaling pathways involving phosphorylation.
“NO activates soluble guanylate cyclase to produce cGMP, which participates in signaling pathways involving phosphorylation (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Kots, 2009, Handb Exp Pharmacol. source
Not checked in the free run.
May combine two claims.
PremisecitationEndothelium-derived NO suppresses platelet adhesion, leukocyte infiltration, and VSMC proliferation and migration.
“Endothelium-derived NO suppresses platelet adhesion, leukocyte infiltration, and VSMC proliferation and migration (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEndothelial synthesis of NO is highly regulated in response to hemodynamic and humoral factors.
“The endothelial synthesis of this potent molecule is highly regulated, in response to hemodynamic (e.g., shear stress) as well as humoral (e.g., serotonin) factors (3).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNO regulates the activities of enzymes and signaling proteins by S-nitrosylation of thiol moieties.
“Furthermore, NO regulates the activities of enzymes and signaling proteins by S-nitrosylation of thiol moieties (2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] source
Not checked in the free run.
May combine two claims.
PremisecitationThe adverse effect of cardiovascular risk factors on the NOS pathway is mediated by asymmetric dimethylarginine and by vascular generation of superoxide anion, which degrades NO to peroxynitrite.
“Their adverse effect on the NOS pathway is mediated by asymmetric dimethylarginine (ADMA; the endogenous antagonist of NO synthesis) and by the vascular generation of superoxide anion (O 2 -), which degrades NO to peroxynitrite anion (ONOO -) (4, 5).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAfter vascular injury, NO biosynthesis as reflected by vascular nitrosothiols was not increased except in the presence of an arginase inhibitor, indicating that l-arginine had become rate limiting for NO production.
“However, NO biosynthesis (as reflected by vascular nitrosothiols) was not increased, except in the presence of an arginase inhibitor, indicating that l-arginine had become rate limiting for NO production.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
May combine two claims.
PremisecitationSubsequent activation of oxidant-sensitive transcriptional pathways increases VSMC proliferation and migration, contributing to the myointimal lesion.
“Subsequent activation of oxidant-sensitive transcriptional pathways increases VSMC proliferation and migration (10), contributing to the myointimal lesion.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
May combine two claims.
Premiseown dataThe benefit of sodium nitrite was associated with a 10-fold increase in NO generation by injured vessels, an effect not attenuated by the NOS inhibitor L-NAME.
“This benefit was associated with a 10-fold increase in NO generation by the injured vessels, an effect that was not attenuated by the NOS inhibitor N-nitro-l-arginine methyl ester (L-NAME).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
May combine two claims.
PremisecitationThe XOR antagonist allopurinol blocked the antiproliferative action of sodium nitrite in vitro and abrogated the therapeutic effect of dietary nitrite on the injured murine carotid artery.
“They observed that the XOR antagonist allopurinol blocked the antiproliferative action of sodium nitrite in vitro and abrogated the therapeutic effect of dietary nitrite on the injured murine carotid artery.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Alef, 2011, J Clin Invest. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThese findings are consistent with previous observations that nitrite may be converted to NO in tissues and in blood, particularly in states of hypoxia and acidosis.
“These findings are consistent with previous observations that nitrite may be converted to NO in tissues and in blood, particularly in states of hypoxia and acidosis (12,13).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningConversion of nitrite to NO by XOR and/or other metabolic pathways could replace or augment endothelial production of NO and thereby inhibit processes known to contribute to atherosclerosis, restenosis, and vascular inflammation.
“The conversion of nitrite to NO by the enzyme XOR (and/or other metabolic pathways as discussed above) could replace or augment endothelial production of NO and thereby inhibit processes known to contribute to atherosclerosis, restenosis, and vascular inflammation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDietary nitrite and nitrate can contribute to the formation of potentially carcinogenic nitrosamines, although the epidemiological association of dietary nitrogen oxides with cancer has been questioned.
“Furthermore, dietary nitrite and nitrate can contribute to the formation of potentially carcinogenic nitrosamines, although the epidemiological association of dietary nitrogen oxides with cancer has been questioned (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] source
Not checked in the free run.
May combine two claims.
PremisecitationNO increases local blood flow and protects the gastric mucosa.
“In any event, NO increases local blood flow and protects the gastric mucosa (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
May combine two claims.
PremisecitationDietary supplementation of nitrites can cause methemoglobinemia and interfere with oxygenation of the blood.
“Dietary supplementation of nitrites can cause methemoglobinemia and interfere with oxygenation of the blood.”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
Acute injury of the vessel wall denudes the endothelial lining and removes homeostatic regulation, precipitating myointimal hyperplasia.
“Acute injury of the vessel wall denudes the endothelial lining, removing homeostatic regulation and precipitating a wave of events leading to myointimal hyperplasia.”
The paper relies on this without support.
After vascular injury, activated VSMCs and infiltrating immune cells express inducible NOS.
“Although the endothelial source of NO generation is lost, the activated VSMCs and the infiltrating immune cells express the inducible form of NOS (iNOS).”
The paper relies on this without support.
Superoxide anion combines with NO to form the cytotoxic radical peroxynitrite.
“Superoxide anion combines with NO to form the cytotoxic radical ONOO -.”
The paper relies on this without support.
Ornithine-derived polyamines stimulate VSMC proliferation.
“Ornithine serves as a precursor for polyamines that are known to stimulate VSMC proliferation.”
The paper relies on this without support.
NO is derived from the metabolism of l-arginine by NOS.
“NO is derived from the metabolism of l-arginine by NOS.”
The paper relies on this without support.
XOR is an enzyme capable of producing NO from nitrite.
“XOR is an enzyme that is capable of producing NO from nitrite.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oral administration of nitrate and nitrite provides protection from ischemia-reperfusion injury.
“protection from ischemia-reperfusion injury[97,98,272]”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [272]
Cites
A Clinical Trial of the Effects of Dietary Patterns on Blood Pressure
Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Sacks, F. M., Bray, G. A., Vogt, T. M., Cutler, J. A., Windhauser, M. M., et al. (1997) · New England Journal of Medicine · doi:10.1056/nejm199704173361601 · Cited by 5,981 · see citing works
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219 · see citing works
<i>DNMT3A</i> Mutations in Acute Myeloid Leukemia
Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1005143 · Cited by 1,983 · see citing works
Xia, Y., Dawson, V. L., Dawson, T. M., Snyder, S. H., & Zweier, J. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6770 · Cited by 718 · see citing works
Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO
Kapil, V., Milsom, A. B., Okorie, M., Maleki-Toyserkani, S., Akram, F., Rehman, F., Arghandawi, S., Pearl, V., Benjamin, N., Loukogeorgakis, S., et al. (2010) · Hypertension · doi:10.1161/hypertensionaha.110.153536 · Cited by 621 · see citing works
Nitrate and nitrite in biology, nutrition and therapeutics
Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.260 · Cited by 617 · see citing works
The myeloproliferative disorders.
Campbell, P., & Green, A. (2006) · New England Journal of Medicine · doi:10.1056/nejmra063728 · Cited by 598 · see citing works
NADPH Oxidases: Functions and Pathologies in the Vasculature
Lassègue, B., & Griendling, K. K. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.181610 · Cited by 592 · see citing works
JAK mutations in high-risk childhood acute lymphoblastic leukemia
Mullighan, C. G., Zhang, J., Harvey, R. C., Collins-Underwood, J. R., Schulman, B. A., Phillips, L. A., Tasian, S. K., Loh, M. L., Su, X., Liu, W., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811761106 · Cited by 558 · see citing works
<i>S</i> -Nitrosylation in Cardiovascular Signaling
Lima, B., Forrester, M. T., Hess, D. T., & Stamler, J. S. (2010) · Circulation Research · doi:10.1161/circresaha.109.207381 · Cited by 490 · see citing works
Recent advances in arginine metabolism: roles and regulation of the arginases
Morris Jr, S. M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00278.x · Cited by 485 · see citing works
Is oxidative stress a therapeutic target in cardiovascular disease?
Münzel, T., Gori, T., Bruno, R. M., & Taddei, S. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq396 · Cited by 470 · see citing works
Asymmetrical Dimethylarginine: The Über Marker?
Cooke, J. P. (2004) · Circulation · doi:10.1161/01.cir.0000126823.07732.d5 · Cited by 396 · see citing works
Self-citationSomatically acquired JAK1 mutations in adult acute lymphoblastic leukemia
Flex, E., Petrangeli, V., Stella, L., Chiaretti, S., Hornakova, T., Knoops, L., Ariola, C., Fodale, V., Clappier, E., Paoloni, F. P., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072182 · Cited by 331 · see citing works
When Does Nitrate Become a Risk for Humans?
Powlson, D. S., Addiscott, T. M., Benjamin, N., Cassman, K. G., de Kok, T. M., van Grinsven, H., L'hirondel, J., Avery, A. A., & van Kessel, C. (2008) · Journal of Environmental Quality · doi:10.2134/jeq2007.0177 · Cited by 313 · see citing works
Tissue Processing of Nitrite in Hypoxia
Feelisch, M., Fernandez, B. O., Bryan, N. S., Garcia-Saura, M. F., Bauer, S., Whitlock, D. R., Ford, P. C., Janero, D. R., Rodriguez, J., & Ashrafian, H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806654200 · Cited by 218 · see citing works
Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers
Jeong, E. G., Kim, M. S., Nam, H. K., Min, C. K., Lee, S., Chung, Y. J., Yoo, N. J., & Lee, S. H. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4839 · Cited by 203 · see citing works
Programming Smooth Muscle Plasticity With Chromatin Dynamics
McDonald, O. G., & Owens, G. K. (2007) · Circulation Research · doi:10.1161/01.res.0000266448.30370.a0 · Cited by 163 · see citing works
Mining for JAK–STAT mutations in cancer
Constantinescu, S. N., Girardot, M., & Pecquet, C. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.12.002 · Cited by 146 · see citing works
Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care
Weitzberg, E., Hezel, M., Lundberg, J. O., & Warner, D. S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181fcf3cc · Cited by 145 · see citing works
Cooke, J. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0430082100 · Cited by 135 · see citing works
Self-citationMechanisms of nitrite reduction to nitric oxide in the heart and vessel wall
Zweier, J. L., Li, H., Samouilov, A., & Liu, X. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.12.004 · Cited by 132 · see citing works
Identification of somatic JAK1 mutations in patients with acute myeloid leukemia.
Xiang, Z.-F., Zhao, Y., Mitaksov, V., Fremont, D., Kasai, Y., Molitoris, A., Ries, R., Miner, T., McLellan, M., Dipersio, J., et al. (2008) · Blood · doi:10.1182/blood-2007-05-090308 · Cited by 108 · see citing works
Alef, M. J., Vallabhaneni, R., Carchman, E., Morris, S. M., Shiva, S., Wang, Y., Kelley, E. E., Tarpey, M. M., Gladwin, M. T., Tzeng, E., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44079 · Cited by 101 · see citing works
Wartman, L. D., Larson, D. E., Xiang, Z., Ding, L., Chen, K., Lin, L., Cahan, P., Klco, J. M., Welch, J. S., Li, C., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45284 · Cited by 99 · see citing works
A Short History of cGMP, Guanylyl Cyclases, and cGMP-Dependent Protein Kinases
Kots, A. Y., Martin, E., Sharina, I. G., & Murad, F. (2009) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-540-68964-5_1 · Cited by 82 · see citing works
Nitrite and nitrate: cardiovascular risk–benefit and metabolic effect
Tang, Y., Jiang, H., & Bryan, N. S. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328341942c · Cited by 69 · see citing works
Oncogenic K-ras cooperates with PML-RAR to induce an acute promyelocytic leukemia-like disease
Chan, I. T. (2006) · Blood · doi:10.1182/blood-2006-04-015040 · Cited by 61 · see citing works
The role of endothelial cells and their progenitors in intimal hyperplasia
Patel, S. D., Waltham, M., Wadoodi, A., Burnand, K. G., & Smith, A. (2010) · Therapeutic Advances in Cardiovascular Disease · doi:10.1177/1753944710362903 · Cited by 59 · see citing works
How patients have benefited from mouse models of acute promyelocytic leukaemia
Lallemand-Breitenbach, V., Zhu, J., Kogan, S. C., Chen, Z., & de Thé, H. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1719 · Cited by 41 · see citing works
Mouse Models of Acute Promyelocytic Leukemia
Kogan, S. C. (2007) · Springer eBooks · doi:10.1007/978-3-540-34594-7_2 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Cooke, J. P., & Ghebremariam, Y. T. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.228833 · Cited by 49 · see citing works
Self-citationProton pump inhibitors and vascular function: A prospective cross-over pilot study
Ghebremariam, Y. T., Cooke, J. P., Khan, F., Thakker, R., Chang, P., Shah, N. H., Nead, K. T., & Leeper, N. J. (2015) · Vascular Medicine · doi:10.1177/1358863x14568444 · Cited by 45 · see citing works
Self-citationEndothelium-Derived Nitric Oxide as an Antiatherogenic Mechanism: Implications for Therapy
Sukhovershin, R. A., Yepuri, G., & Ghebremariam, Y. T. (2015) · Methodist DeBakey Cardiovascular Journal · doi:10.14797/mdcj-11-3-166 · Cited by 46 · see citing works
Self-citationThe Potential of Flavanol and Procyanidin Intake to Influence Age-Related Vascular Disease
Holt, R. R., Heiß, C., Kelm, M., & Keen, C. L. (2012) · Journal of Nutrition in Gerontology and Geriatrics · doi:10.1080/21551197.2012.702541 · Cited by 34 · see citing works
Stefano, G. B., & Kream, R. M. (2011) · Medical Science Monitor · doi:10.12659/msm.881972 · Cited by 27 · see citing works
Ghebremariam, Y. T., Yamada, K., Lee, J. C., Johnson, C. L. C., Atzler, D., Anderssohn, M., Agrawal, R., Higgins, J., Patterson, A. J., Böger, R. H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060653 · Cited by 26 · see citing works
Self-citationEnhancing Stent Effectiveness with Nanofeatures
Bassous, N. J., Cooke, J. P., & Webster, T. J. (2016) · Methodist DeBakey Cardiovascular Journal · doi:10.14797/mdcj-12-3-163 · Cited by 21 · see citing works
Self-citationModulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers
Lai, L., & Ghebremariam, Y. T. (2015) · Journal of Diabetes Research · doi:10.1155/2016/1982096 · Cited by 20 · see citing works
Self-citationAsymmetric Dimethylarginine, Race, and Mortality in Hemodialysis Patients
Drew, D. A., Tighiouart, H., Scott, T. M., Kantor, A., Fan, L., Artusi, C., Plebani, M., Weiner, D. E., & Sarnak, M. J. (2014) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.00770114 · Cited by 16 · see citing works
Srdanovic, I. (2021) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/jpps32053 · Cited by 12 · see citing works
Characterization of a Fluorescent Probe for Imaging Nitric Oxide
Ghebremariam, Y. T., Huang, N. F., Kambhampati, S., Volz, K. S., Joshi, G. G., Anslyn, E. V., & Cooke, J. P. (2013) · Journal of Vascular Research · doi:10.1159/000356445 · Cited by 12 · see citing works
Self-citationImpact of mitochondrial nitrite reductase on hemodynamics and myocardial contractility
Dungel, P., Penzenstadler, C., Ashmwe, M., Dumitrescu, S., Stögerer, T., Redl, H. R., Bahrami, S., & Kozlov, A. V. (2017) · Scientific Reports · doi:10.1038/s41598-017-11531-3 · Cited by 8 · see citing works
Content of nitric oxide and glycative compounds in cured meat products-Negative impact upon health
Yang, Y., Wang, Z., & Yin, M. (2018) · Biomedicine · doi:10.1051/bmdcn/2018080210 · Cited by 6 · see citing works
Methyl donor diet attenuates intimal hyperplasia after vascular injury in rats
Jiang, Q.-L., Li, T., Xu, Q., Zeng, Y., Wang, W., Zhang, B., Yao, Q., Jiang, J., & Jiang, J. (2023) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2023.109486 · Cited by 3 · see citing works
Alharbi, M., Stephan, B. C. M., Shannon, O. M., & Siervo, M. (2023) · Nutrition & Metabolism · doi:10.1186/s12986-023-00766-9 · Cited by 3 · see citing works
Arterial Wall Remodeling and Restenosis Following Vascular Reconstruction
Ma, X., & Geary, R. L. (2013) · Springer eBooks · doi:10.1007/978-1-4471-4429-8_14
Srdanovic, I. (2022) · Pharmaceutics and Pharmacology Research · doi:10.31579/2693-7247/061
A Long-lived Avatar for Modeling Age-Related Vascular DiseasePreprint
Qin, W., Tran, T. N., Xiao, Y., Ta, K., Kandel, I., Kumar, A., Pandey, R., Dongchau, B. M., Shah, V. V., Nguyen, T. K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.29.721776
Self-citation
- Authors
- Cooke, J. P., & Ghebremariam, Y. T.
- Affiliations
- Stanford Cardiovascular Institute (US)
- Corresponding author
- Cooke, John P.
- ORCID
- Cooke, John P.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-04-01
- Volume
- 121
- Issue
- 4
- Pages
- 1258-1260
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3069795
- OpenAlex
- W1981465993
- Semantic Scholar
- 4e8f81602c56863873d0d33cfe8557f34cb86f0c
- Cited by
- 19
- References
- 31
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tobacco-Related Disease Research Program
- National Institutes of Health
- Stanford Bio-X
- National Heart, Lung, and Blood Institute (U01HL100397, RC2HL103400, K12HL087746)
- Stanford Cardiovascular Institute, School of Medicine, Stanford University
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- dietary nitrate, nitric oxide, restenosis, xanthine oxidoreductase, nitrite, myointimal hyperplasia, vascular injury, endothelium, nitric oxide synthase, vascular smooth muscle cells
- MeSH terms
- Animals, Diet, Endothelium, Vascular, Homeostasis, Hyperplasia, Models, Biological, Nitrates, Nitric Oxide, Nitrites, Tunica Intima, Coronary Restenosis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
