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Cited by 464Nitric Oxide and Endothelin EffectsLipoproteins and Cardiovascular HealthAtherosclerosis and Cardiovascular Diseases

Association of Nitrotyrosine Levels With Cardiovascular Disease and Modulation by Statin Therapy

Shishehbor, Mehdi H., Aviles, Ronnier J., Brennan, Marie-Luise, Fu, Xiaoming, Goormastic, Marlene, Pearce, Gregory L., Gokce, Noyan, Keaney, John F. +4 more·2003·JAMA
DOI 10.1001/jama.289.13.1675
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Abstract

Context: Formation of nitric oxide–derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide–derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma. Objectives: To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy. Design, Setting, and Patients: A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For the case-control study, 100 case-patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol ≥130 mg/dL [≥3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy. Main Outcome Measures: In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels. Results: Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 µmol/mol [interquartile range, 4.8-13.8 µmol/mol] tyrosine vs 5.2 µmol/mol [interquartile range, 2.2-8.4 µmol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP. Conclusions: The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide–derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.

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Authors
Shishehbor, M. H., Aviles, R. J., Brennan, M.-L., Fu, X., Goormastic, M., Pearce, G. L., Gokce, N., Keaney, J. F., Penn, M. S., Sprecher, D. L., Vita, J. A., & Hazen, S. L.
Affiliations
  • Cleveland Clinic (US)
  • Boston University (US)
Corresponding author
Hazen, Stanley L.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2003-04-02
Volume
289
Issue
13
Pages
1675
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.289.13.1675
OpenAlex
W2138382873
Cited by
464
References
43
Citations by year
2026: 9 · 2025: 8 · 2024: 11 · 2023: 11 · 2022: 18 · 2021: 12 · 2020: 12 · 2019: 17 · 2018: 9 · 2017: 11 · 2016: 15 · 2015: 14 · 2014: 14 · 2013: 20 · 2012: 18
FWCI
26.83
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL61878, P01HL060886, HL 62526, R01HL061878, HL 70621, R01HL062526, R01HL070621, HL-60886)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
nitrotyrosine, coronary artery disease, statin therapy, atorvastatin, atherosclerosis, inflammation, C-reactive protein, hypercholesterolemia, LDL cholesterol, lipid-lowering therapy, cardiovascular risk markers, protein oxidation, statins, cardiovascular disease prevention
MeSH terms
Atorvastatin, Adult, Aged, Anticholesteremic Agents, C-Reactive Protein, Cardiovascular Diseases, Coronary Artery Disease, Female, Heptanoic Acids, Humans, Hypercholesterolemia, Lipoproteins, Male, Middle Aged, Prospective Studies, Pyrroles, Risk Factors, Tyrosine, Case-Control Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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