title: Lp(a)/apo(a) modulate MMP-9 activation and neutrophil cytokines in vivo in inflammation to regulate leukocyte recruitment.
abstract: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular diseases, but the mechanism is unclear. The pathogenic risk of Lp(a) is associated with elevated plasma concentration, small isoforms of apolipoprotein [apo(a)], the unique apolipoprotein of Lp(a), and a mimic of plasminogen. Inflammation is associated with both the initiation and recovery of cardiovascular diseases, and plasminogen plays an important role in leukocyte recruitment. Because Lp(a)/apo(a) is expressed only in primates, transgenic mice were generated, apo(a)tg and Lp(a)tg mice, to determine whether Lp(a)/apo(a) modifies plasminogen-dependent leukocyte recruitment or whether apo(a) has an independent role in vivo. Plasminogen activation was markedly reduced in apo(a)tg and Lp(a)tg mice in both peritonitis and vascular injury inflammatory models, and was sufficient to reduce matrix metalloproteinase-9 activation and macrophage recruitment. Furthermore, neutrophil recruitment and the neutrophil cytokines, CXCL1/CXCL2, were suppressed in apo(a)tg mice in the abdominal aortic aneurysm model. Reconstitution of CXCL1 or CXCL2 restored neutrophil recruitment in apo(a)tg mice. Apo(a) in the plasminogen-deficient background and Lp(a)tg mice were resistant to inhibition of macrophage recruitment that was associated with an increased accumulation of apo(a) in the intimal layer of the vessel wall. These data indicate that, in inflammation, Lp(a)/apo(a) suppresses neutrophil recruitment by plasminogen-independent cytokine inhibition, and Lp(a)/apo(a) inhibits plasminogen activation and regulates matrix metalloproteinase-9 activation and macrophage recruitment.
authors.affiliation: Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Menggui
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Jessica
authors.initials: J
authors.lastname: Grondolsky
authors.affiliation: Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland, Ohio. Electronic address: hooverj@ccf.org.
authors.forename: Jane
authors.initials: J
authors.lastname: Hoover-Plow
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000473:pathology; D001055:Apolipoproteins B / Q000378:metabolism; D053241:Apoprotein(a) / Q000378:metabolism*; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009500:Neutralization Tests; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D010538:Peritonitis / Q000473:pathology; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D010958:Plasminogen; D053241:Apoprotein(a); D005341:Fibrinolysin; D020780:Matrix Metalloproteinase 9