Published online before print July 5, 2007, doi: 10.1161/CIRCRESAHA.107.157537
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Submitted on April 17, 2007
Revised on June 8, 2007
Accepted on June 25, 2007
Increased Protein Nitration Burden in the Atherosclerotic Lesions and Plasma of Apolipoprotein A-I-Deficient Mice
Ioannis Parastatidis ;
From the Stokes Research Institute and Departments of Pediatrics and Pharmacology (I.P., L.T., D.M.F., H.I.), Children’s Hospital of Philadelphia and The University of Pennsylvania, Philadelphia; the Department of Medicine (R.E.M., J.T., D.J.R.), The University of Pennsylvania, Philadelphia; the Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention (X.F., S.L.H.), Cleveland Clinic Foundation, Cleveland Ohio; the Laboratory of Clinical Chemistry and Hematology and Cell Microscopy Center (H.F.G.H.), University Medical Center Utrecht, and Institute for Biomembranes, Utrecht, The Netherlands; the Department of Biochemistry and Mass Spectrometry Research Center (M.K.D., D.C.L.), Vanderbilt University School of Medicine, Nashville, Tenn; and the Department of Biological Chemistry (I.P.), School of Medicine, Aristotle University of Thessaloniki, Greece. Permanent address for L.T.: Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. Current address for D.M.F.: Ministry of Health, Sao Paulo, SP, Brazil.
* To whom correspondence should be addressed. E-mail: ischirop{at}mail.med.upenn.edu.
Apolipoprotein A-I (apoA-I), the major protein constituent within high-density lipoprotein (HDL), has been associated with antiatherogenic protection by mechanisms that include reverse cholesterol transport and antiinflammatory functions. To evaluate the proposed protective function of apoA-I, proteins modified by nitrating oxidants were evaluated in the aortic tissue and plasma of mice lacking the low-density lipoprotein receptor and apobec (LA) and LA mice with genetic deletion of apoA-I (LA-apoA-I-/-). The levels of nitrated proteins in aortic tissue quantified by liquid chromatography with online electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) were 6-fold higher in the LA-apoA-I-/- as compared with the LA mice. The quantitative analyses were corroborated by immunohistochemical and high-resolution immunoelectron microscopic evaluation of the lesions, which revealed abundant staining for nitrated proteins in the aortic root lesions of LA-apoA-I-/- as compared with the LA mice. Proteomic approaches based on affinity enrichment and site-specific adduct mapping identified unique specific protein targets for nitration in the plasma of LA-apoA-I-/- that were not present in the plasma of LA mice. In particular the nitration of fibrinogen was shown to accelerate fibrin clot formation. Another consequence of the augmented levels of nitrated proteins was the induction of humoral responses documented by the increased circulating immunoglobulins that recognize nitrotyrosine in LA-apoA-I-/- as compared with the LA mice. These data collectively support a protective function of apoA-I diminishing the burden of nitrative oxidants in these mice models of atherosclerosis.
Key words: atherosclerosis • tyrosine nitration • proteomics
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