A physiological function for apolipoprotein(a): a natural regulator of the inflammatory response.
Structural similarities between apolipoprotein(a) (apo(a)), the unique apoprotein of lipoprotein(a), and plasminogen, the zymogen of plasmin, can interfere with functions of plasmin (ogen) in vitro. The purpose of this study was to evaluate the role of apo(a) in inflammation in vivo using apo(a) transgenic mice and to determine if effects are plasminogen-dependent using backgrounds that are either plasminogen-replete or plasminogen-deficient. After administration of peritoneal inflammatory stimuli, thioglycollate, bioimplants or lipopolysaccharide, the number of responding peritoneal neutrophils and macrophages were quantified. Apo(a), in either wild-type or plasminogen deficient backgrounds, inhibited neutrophil recruitment but had no effect on plasminogen-dependent macrophage recruitment. Macrophage-inflammatory protein-2, a neutrophil chemokine, was reduced in apo(a) mice, and injection of this chemokine prior to thioglycollate restored neutrophil recruitment in apo(a) transgenic mice. In the lipopolysaccharide model, mice with apo(a), unlike mice without apo(a), did not increase neutrophil recruitment in response to the stimulus. In the bioimplant model, neutrophil recruitment and neutrophil cytokines were reduced in apo(a)tg mice but only in a plasminogen-deficient background. These results indicate for the first time that apo(a), independent of plasminogen interaction, inhibits neutrophil recruitment in vivo in diverse peritoneal inflammatory models. Hence, apo(a) may function as a cell specific suppressor of the inflammatory response.
Hoover-Plow
Jane
J
Department of Molecular Cardiology, NB50, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA. hooverj@ccf.org
Hart
Erika
E
Gong
Yanqing
Y
Shchurin
Aleksey
A
Schneeman
Tracey
T
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D054426:Chemokine CXCL2 / Q000097:blood; D016207:Cytokines / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology; D010958:Plasminogen / Q000172:deficiency*
D001054:Apolipoproteins A; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D010958:Plasminogen