Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition.
BACKGROUND
We examine the relationship of related posttranslational modification products of arginine methylation and coronary artery disease (CAD) phenotypes.


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.
Wang
Zeneng
Z
Center for Cardiovascular Diagnostics and Prevention, Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Tang
W H Wilson
WH
Cho
Leslie
L
Brennan
Danielle M
DM
Hazen
Stanley L
SL
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000401:mortality; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000150:complications / Q000201:enzymology / Q000401:mortality; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D055432:Metabolomics / Q000379:methods; D008745:Methylation; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016017:Odds Ratio; D009952:Ornithine / Q000097:blood; D011379:Prognosis; D011446:Prospective Studies; D011499:Protein Processing, Post-Translational; D018570:Risk Assessment; D012307:Risk Factors; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000097:blood
D015415:Biomarkers; D019323:omega-N-Methylarginine; D002956:Citrulline; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D003404:Creatinine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D008239:Lysine