Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin.
Lipoprotein(a) [Lp(a)], consisting of LDL and the unique constituent apolipoprotein(a) [apo(a)], which contains multiple repeats resembling plasminogen kringle 4, is considered a risk factor for the development of atherosclerotic disorders. However, the underlying mechanisms for the atherogenicity of Lp(a) are not completely understood. Here, we define a novel function of Lp(a) in promoting inflammatory cell recruitment that may contribute to its atherogenicity. Through its apo(a) moiety Lp(a) specifically interacts with the beta2-integrin Mac-1, thereby promoting the adhesion of monocytes and their transendothelial migration in a Mac-1-dependent manner. Interestingly, the interaction between Mac-1 and Lp(a) was strengthened in the presence of proatherogenic homocysteine and was blocked by plasminogen/angiostatin kringle 4. Through its interaction with Mac-1, Lp(a) induced activation of the proinflammatory transcription factor NFkappaB, as well as the NFkappaB-related expression of prothrombotic tissue factor. In atherosclerotic coronary arteries Lp(a) was found to be localized in close proximity to Mac-1 on infiltrating mononuclear cells. Taken together, our data demonstrate that Lp(a), via its apo(a) moiety, is a ligand for the beta2-integrin Mac-1, thereby facilitating inflammatory cell recruitment to atherosclerotic plaques. These observations suggest a novel mechanism for the atherogenic properties of Lp(a).
Sotiriou
Sotirios N
SN
Experimental Immunology Branch, NCI, NIH, Bethesda, Maryland 20892, USA.
Orlova
Valeria V
VV
Al-Fakhri
Nadia
N
Ihanus
Eveliina
E
Economopoulou
Matina
M
Isermann
Berend
B
Bdeir
Khalil
K
Nawroth
Peter P
PP
Preissner
Klaus T
KT
Gahmberg
Carl G
CG
Koschinsky
Marlys L
ML
Chavakis
Triantafyllos
T
D000368:Aged; D000369:Aged, 80 and over; D015119:Aminocaproic Acid / Q000494:pharmacology; D043168:Angiostatins / Q000494:pharmacology; D001054:Apolipoproteins A / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D050197:Atherosclerosis / Q000503:physiopathology*; D002465:Cell Movement; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000737:chemistry / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017270:Lipoprotein(a) / Q000494:pharmacology / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010958:Plasminogen / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014162:Transfection
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D006710:Homocysteine; D018799:Intercellular Adhesion Molecule-1; D043168:Angiostatins; D010958:Plasminogen; D001241:Aspirin; D015119:Aminocaproic Acid