Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac‐1 integrin

Abstract

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).

CD40 Ligand Mediates Inflammation Independently of CD40 by Interaction With Mac-1

“…46 Interestingly, Mac-1 binds to several other ligands apart from intracellular cell adhesion molecule-1, such as fibrinogen, lipoprotein (a), Thy-1 (CD90), receptor of advanced glycation end products, and vitronectin. 19,27,[47][48][49] Notably, several of these ligands associate with leukocyte adhesion/transmigration as well as atherogenesis.…”

“…Mac-1 is a highly promiscuous receptor that interacts with ligands such as C3bi, 16 intracellular adhesion molecule-1, 17 fibrinogen, 18 vitronectin, 19 factor Xa, 20,21 heparin, 22,23 GP Ib␣, 24,25 JAM-3, 26 and lipoprotein (a). 27 Based on these interactions, Mac-1 participates in processes important in atherosclerosis such as inflammation, immune response, and coagulation. 28 -31 Therefore, we further tested the hypothesis that CD40L interacts with the monocyte/macrophage integrin Mac-1.…”

Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a)

“…Lp(a)/apo(a) also promotes the assembly of actin stress fi bers resulting in cell contraction and increased endothelial cell permeability ( 17 ). Lp(a)/apo(a) has been implicated in pro-infl ammatory processes through its ability to bind to the integrin, Mac-1, on leukocytes, resulting in the Mac-1-dependent promotion of monocyte adhesion and transendothelial migration ( 18 ). The apo(a) component of Lp(a) has been shown to induce gene expression in THP-1 macrophages, including the upregulation of IL-8 expression; this effect was mapped to the carboxyl-terminal half of the apo(a) protein, with a role for the KV domain suggested ( 19 ).…”

Functional Interaction of CD154 Protein with α5β1 Integrin Is Totally Independent from Its Binding to αIIbβ3 Integrin and CD40 Molecules

“…Additionally, the leukocyte ␣M␤2 integrin (also named Mac-1) has also been identified as a receptor for CD154 (16,17). This integrin was found to be implicated in atherosclerosis development via its role in leukocyte adhesion to the endothelial layer and their subsequent trans-endothelial migration (18). Taken together, these results clearly indicate that CD154 interacts with four different receptors (CD40, ␣IIb␤3, ␣5␤1, and ␣M␤2) of biological relevance.…”