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Isolevuglandin Peptide Modification and Proteasomal Processing Contribute to Autoimmune‐Mediated Hypertension
Author(s) -
Patrick David M.,
Xiao Liang,
Barbaro Natalia R.,
Ao Mingfang,
Ormseth Michelle J.,
Stein C. Michael,
Kirabo Annet,
Harrison David G.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.718.19
Subject(s) - cd86 , cd11c , antigen presentation , chemistry , proteasome , dendritic cell , major histocompatibility complex , immune system , population , antigen presenting cell , immunology , mhc class ii , t cell , biology , biochemistry , medicine , phenotype , environmental health , gene
An estimated one‐third of the world's population suffers from hypertension. Over the last decade, it has become clear that immune activation contributes to hypertension. Reactive oxygen species (ROS) have been shown to be an important activator of this disease. Isolevuglandins (isoLG) are oxidation products of fatty acids that form as a result of ROS. These molecules adduct covalently to lysine residues of proteins. These modified proteins are presented within the major histocompatibility complex type I (MHC‐I) molecule and activate T‐cells, implying a role of the proteasome in peptide processing. We hypothesized that isoLG‐adducted peptides contribute to hypertension in SLE and that presentation of isoLG within antigen presenting cells is dependent on proteasomal processing. We found that isoLG‐adducted peptides are markedly enriched in CD11c positive monocytes of patients with systemic lupus erythematosus (SLE). Moreover, cells that display both the monocyte marker CD11c and the activated dendritic cell marker CD86 were also enriched with isoLG‐adducts in patients with SLE. This implies that isoLGs may be participating in activation of antigen presenting cells in SLE. In addition to these studies, we found that the proteasome contributes to the presentation of isoLG‐adducted peptides on the surface of dendritic cells. We previously showed that treatment of mouse dendritic cells with the oxidant tert‐butyl hydroperoxide confers isoLG‐mediated sensitivity to hypertensive stimulus in recipient mice. Interestingly, co‐treatment of mouse dendritic cells with TBHP and proteasome inhibitor attenuates surface isoLG presentation without modification of intracellular isoLG. Moreover, using a novel method employing fluorescence resonance energy transfer (FRET), we found that isoLG‐adducted peptides and MHC‐I interact at the intermolecular level on mouse dendritic cells, strongly suggesting that these peptides are indeed presented within MHC‐I molecules. Co‐treatment of these cells with TBHP and proteasome inhibitor significantly reduced the intermolecular interaction of isoLG with MHC‐I. These studies provide novel insight into the mechanism of isoLG‐mediated hypertension. Additionally, they suggest a novel role for proteasome inhibitors in the treatment of this condition. Support or Funding Information This work was supported by the Clinical Pharmacology T32 PHS Grant Number 2 T32 GM 7569‐42 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .