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Journal of Lipid Research, Vol. 49, 847-855, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Jonathan W. C. Brock^*, Alicia J. Jenkins^,,**, Timothy J. Lyons^,**, Richard L. Klein, Eunsil Yim, Maria Lopes-Virella, Rickey E. Carter (DCCT/EDIC) Research Group^2,, Suzanne R. Thorpe^*, John W. Baynes^1,*

^* Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC
Department of Endocrinology and Medical Genetics, Medical University of South Carolina, Charleston, SC
Department of Epidemiology and Biostatistics, Medical University of South Carolina, Charleston, SC
Department of Medicine, St. Vincent's, University of Melbourne, Melbourne, Australia
National Institutes of Health, Bethesda, MD
^** Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Published, JLR Papers in Press, January 17, 2008.

² Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Complication (DCCT/EDIC) Research Group are listed in the Appendix.

¹ To whom correspondence should be addressed. e-mail: john.baynes{at}sc.edu

Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q⁸⁴-M⁸⁶-K⁸⁸, W¹⁰⁸-M¹¹²-R¹¹⁶, and L¹⁴⁴-M¹⁴⁸-R¹⁴⁹. These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met⁸⁶, Met¹¹², and Met¹⁴⁸) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N-malondialdehyde-lysine or N-(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.

Supplementary key words apolipoprotein A-I • high density lipoprotein • oxidation • oxidative stress

Abbreviations: ACE, angiotensin-converting enzyme; AER, albumin excretion rate; apoA-I, apolipoprotein A-I; CVD, cardiovascular disease; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; HODE, hydroxyoctadecadienoic acid; LPO, lipid peroxide; Met, methionine; Met(O), methionine sulfoxide; PON-1, paraoxonase; Q-TOF, quadrupole time-of-flight; RA, relative area; SLO, soybean lipoxygenase; TIC, total ion chromatogram; T1DM, type 1 diabetes mellitus; XIC, extracted ion chromatogram