Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration

Stephan Baldus, Jason P. Eiserich, Alireza Mani, Laura Castro, Mario Figueroa, Phillip Chumley, Ma Wenxin, Albert Tousson, C. Roger White, Daniel C. Bullard, Marie Luise Brennan, Aldons J. Lusis, Kevin P. Moore, Bruce A. Freeman

Research output: Contribution to journalArticle

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Abstract

Nitrotyrosine formation is a hallmark of vascular inflammation, with polymorphonuclear neutrophil-derived (PMN-derived) and monocyte-derived myeloperoxidase (MPO) being shown to catalyze this posttranslational protein modification via oxidation of nitrite (NO2 -) to nitrogen dioxide (NO2). Herein, we show that MPO concentrates in the subendothelial matrix of vascular tissues by a transcytotic mechanism and serves as a catalyst of ECM protein tyrosine nitration. Purified MPO and MPO released by intraluminal degranulation of activated human PMNs avidly bound to aortic endothelial cell glycosaminoglycans in both cell monolayer and isolated vessel models. Cell-bound MPO rapidly transcytosed intact endothelium and colocalized abluminally with the ECM protein fibronectin. In the presence of the substrates hydrogen peroxide (H2O2) and NO2 -, cell and vessel wall-associated MPO catalyzed nitration of ECM protein tyrosine residues, with fibronectin identified as a major target protein. Both heparin and the low-molecular weight heparin enoxaparin significantly inhibited MPO binding and protein nitrotyrosine (NO2Tyr) formation in both cultured endothelial cells and rat aortic tissues. MPO-/- mice treated with intraperitoneal zymosan had lower hepatic NO2Tyr/tyrosine ratios than did zymosan-treated wild-type mice. These data indicate that MPO significantly contributes to NO2Tyr formation in vivo. Moreover, transcytosis of MPO, occurring independently of leukocyte emigration, confers specificity to nitration of vascular matrix proteins.

Original languageEnglish (US)
Pages (from-to)1759-1770
Number of pages12
JournalJournal of Clinical Investigation
Volume108
Issue number12
DOIs
StatePublished - 2001

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Transcytosis
Peroxidase
Blood Vessels
Tyrosine
Proteins
Zymosan
Fibronectins
Endothelial Cells
Enoxaparin
Nitrogen Dioxide
Low Molecular Weight Heparin
Emigration and Immigration
Post Translational Protein Processing
Nitrites
Glycosaminoglycans
Cell Wall
Hydrogen Peroxide
Endothelium
Heparin
Monocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Baldus, S., Eiserich, J. P., Mani, A., Castro, L., Figueroa, M., Chumley, P., ... Freeman, B. A. (2001). Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. Journal of Clinical Investigation, 108(12), 1759-1770. https://doi.org/10.1172/JCI200112617

Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. / Baldus, Stephan; Eiserich, Jason P.; Mani, Alireza; Castro, Laura; Figueroa, Mario; Chumley, Phillip; Wenxin, Ma; Tousson, Albert; Roger White, C.; Bullard, Daniel C.; Brennan, Marie Luise; Lusis, Aldons J.; Moore, Kevin P.; Freeman, Bruce A.

In: Journal of Clinical Investigation, Vol. 108, No. 12, 2001, p. 1759-1770.

Research output: Contribution to journalArticle

Baldus, S, Eiserich, JP, Mani, A, Castro, L, Figueroa, M, Chumley, P, Wenxin, M, Tousson, A, Roger White, C, Bullard, DC, Brennan, ML, Lusis, AJ, Moore, KP & Freeman, BA 2001, 'Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration', Journal of Clinical Investigation, vol. 108, no. 12, pp. 1759-1770. https://doi.org/10.1172/JCI200112617
Baldus, Stephan ; Eiserich, Jason P. ; Mani, Alireza ; Castro, Laura ; Figueroa, Mario ; Chumley, Phillip ; Wenxin, Ma ; Tousson, Albert ; Roger White, C. ; Bullard, Daniel C. ; Brennan, Marie Luise ; Lusis, Aldons J. ; Moore, Kevin P. ; Freeman, Bruce A. / Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. In: Journal of Clinical Investigation. 2001 ; Vol. 108, No. 12. pp. 1759-1770.
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T1 - Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration

AU - Baldus, Stephan

AU - Eiserich, Jason P.

AU - Mani, Alireza

AU - Castro, Laura

AU - Figueroa, Mario

AU - Chumley, Phillip

AU - Wenxin, Ma

AU - Tousson, Albert

AU - Roger White, C.

AU - Bullard, Daniel C.

AU - Brennan, Marie Luise

AU - Lusis, Aldons J.

AU - Moore, Kevin P.

AU - Freeman, Bruce A.

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N2 - Nitrotyrosine formation is a hallmark of vascular inflammation, with polymorphonuclear neutrophil-derived (PMN-derived) and monocyte-derived myeloperoxidase (MPO) being shown to catalyze this posttranslational protein modification via oxidation of nitrite (NO2 -) to nitrogen dioxide (NO2). Herein, we show that MPO concentrates in the subendothelial matrix of vascular tissues by a transcytotic mechanism and serves as a catalyst of ECM protein tyrosine nitration. Purified MPO and MPO released by intraluminal degranulation of activated human PMNs avidly bound to aortic endothelial cell glycosaminoglycans in both cell monolayer and isolated vessel models. Cell-bound MPO rapidly transcytosed intact endothelium and colocalized abluminally with the ECM protein fibronectin. In the presence of the substrates hydrogen peroxide (H2O2) and NO2 -, cell and vessel wall-associated MPO catalyzed nitration of ECM protein tyrosine residues, with fibronectin identified as a major target protein. Both heparin and the low-molecular weight heparin enoxaparin significantly inhibited MPO binding and protein nitrotyrosine (NO2Tyr) formation in both cultured endothelial cells and rat aortic tissues. MPO-/- mice treated with intraperitoneal zymosan had lower hepatic NO2Tyr/tyrosine ratios than did zymosan-treated wild-type mice. These data indicate that MPO significantly contributes to NO2Tyr formation in vivo. Moreover, transcytosis of MPO, occurring independently of leukocyte emigration, confers specificity to nitration of vascular matrix proteins.

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