| Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition. | |
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MedLine Citation:
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PMID: 19542023 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: We examine the relationship of related posttranslational modification products of arginine methylation and coronary artery disease (CAD) phenotypes. METHODS AND RESULTS: Plasma was isolated from 1011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization, and future major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 years were investigated. Plasma levels of asymmetrical dimethylarginine (ADMA, endogenous nitric oxide synthase [NOS] inhibitor), symmetrical dimethylarginine (SDMA, which lacks NOS inhibitory activity), N-mono-methylarginine (MMA, a potent NOS inhibitor), methyl-lysine (Methyl-Lys, an unrelated methylated amino acid), arginine, and its major catabolites (citrulline and ornithine) were quantified simultaneously by stable isotope dilution HPLC with online electrospray ionization tandem mass spectrometry and adjusted for traditional risk factors, C-reactive protein, and estimated creatinine clearance. High SDMA levels (adjusted odds ratio [OR] 1.6, 95%CI, 1.1 to 2.6, P<0.001), low MMA (adjusted OR 0.5, 95%CI 0.4 to 0.8, P=0.007), but not ADMA (adjusted OR 1.3, 95%CI 0.88 to 2.0, P=0.177) were associated with increased prevalence of significantly obstructive CAD. Elevated levels of SDMA (adjusted Hazard Ratio [HR] 2.4, 95%CI 1.2 to 4.6, P=0.009), ADMA (adjusted HR 2.2, 95%CI 1.2 to 4.0, P=0.015), as well as an integrated index of arginine methylation [ArgMI=(ADMA+SDMA)/MMA] (adjusted HR 2.4, 95%CI 1.3 to 4.5, P=0.006) were significant independent predictors of incident MACE. ArgMI was predictive of incident MACE even following adjustments for global arginine bioavailability, particularly within secondary prevention patients. CONCLUSIONS: ADMA, SDMA, and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes. |
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Authors:
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Zeneng Wang; W H Wilson Tang; Leslie Cho; Danielle M Brennan; Stanley L Hazen |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-06-18 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 29 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-08-20 Completed Date: 2009-09-08 Revised Date: 2013-06-02 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1383-91 Citation Subset: IM |
Affiliation:
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Center for Cardiovascular Diagnostics and Prevention, Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aged Arginine / analogs & derivatives, blood* Biological Markers / blood C-Reactive Protein / metabolism Cardiovascular Diseases / blood, etiology*, mortality Chromatography, High Pressure Liquid Citrulline / blood Coronary Artery Disease / blood*, complications, enzymology, mortality Creatinine / blood Female Humans Lysine / analogs & derivatives, blood Male Metabolomics* / methods Methylation Middle Aged Nitric Oxide Synthase / antagonists & inhibitors*, metabolism Odds Ratio Ornithine / blood Prognosis Prospective Studies Protein Processing, Post-Translational* Risk Assessment Risk Factors Spectrometry, Mass, Electrospray Ionization Tandem Mass Spectrometry Time Factors omega-N-Methylarginine / blood |
| Grant Support | |
ID/Acronym/Agency:
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1UL1RR024989/RR/NCRR NIH HHS; P01 HL076491-05/HL/NHLBI NIH HHS; P01 HL076491-055328/HL/NHLBI NIH HHS; P01 HL087018/HL/NHLBI NIH HHS; P01 HL087018-020001/HL/NHLBI NIH HHS; P01 HL087018-020001/HL/NHLBI NIH HHS; P50 HL077107-050004/HL/NHLBI NIH HHS; P50 HL077107-050004/HL/NHLBI NIH HHS; UL1 RR024989/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Biological Markers; 17035-90-4/omega-N-Methylarginine; 30315-93-6/N,N-dimethylarginine; 30344-00-4/N,N'-dimethylarginine; 372-75-8/Citrulline; 56-87-1/Lysine; 60-27-5/Creatinine; 7006-33-9/Ornithine; 74-79-3/Arginine; 9007-41-4/C-Reactive Protein; EC 1.14.13.39/Nitric Oxide Synthase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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