Homocysteine enhances superoxide anion release and NADPH oxidase assembly by human neutrophils. Effects on MAPK activation and neutrophil migration.
Hyperhomocysteinaemia has recently been recognized as a risk factor of cardiovascular disease. However, the action mechanisms of homocysteine (Hcy) are not well understood. Given that Hcy may be involved in the recruitment of monocytes and neutrophils to the vascular wall, we have investigated the role of Hcy in essential functions of human neutrophils. We show that Hcy increased superoxide anion (O2*-) release by neutrophils to the extracellular medium, and that this effect was inhibited by superoxide dismutase and diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase activity. The enzyme from rat peritoneal macrophages displayed a similar response. These effects were accompanied by a time-dependent increased translocation of p47phox and p67phox subunits of NADPH oxidase to the plasma membrane. We also show that Hcy increased intracellular H2O2 production by neutrophils, that Hcy enhanced the activation and phosphorylation of mitogen-activated protein kinases (MAPKs), specifically p38-MAPK and ERK1/2, and that the migration of neutrophils was increased by Hcy. Present results are the first evidence that Hcy enhances the oxidative stress of neutrophils, and underscore the potential role of phagocytic cells in vascular wall injury through O2*- release in hyperhomocysteinaemia conditions.
Alvarez-Maqueda
Moisés
M
Departamento de Bioquímica Médica y Biología Molecular, Universidad de Sevilla, Avda. Sánchez Pizjuán 4, 41009 Sevilla, Spain.
El Bekay
Rajaa
R
Monteseirín
Javier
J
Alba
Gonzalo
G
Chacón
Pedro
P
Vega
Antonio
A
Santa María
Consuelo
C
Tejedo
Juan R
JR
Martín-Nieto
José
J
Bedoya
Francisco J
FJ
Pintado
Elisabeth
E
Sobrino
Francisco
F
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D017737:Macrophages, Peritoneal / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D009861:Onium Compounds; D006710:Homocysteine; D013481:Superoxides; C007517:diphenyleneiodonium; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases