Increased Protein Nitration Burden in the Atherosclerotic Lesions and Plasma of Apolipoprotein A-I–Deficient Mice

Author:

Parastatidis Ioannis1,Thomson Leonor1,Fries Diana M.1,Moore Ryan E.1,Tohyama Junichiro1,Fu Xiaoming1,Hazen Stanley L.1,Heijnen Harry F.G.1,Dennehy Michelle K.1,Liebler Daniel C.1,Rader Daniel J.1,Ischiropoulos Harry1

Affiliation:

1. 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...

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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