Accumulation Of Low-density Lipoprotein Research Articles

Prevention of oxLDL uptake leads to decreased atherosclerosis in hematopoietic NPC1-deficient Ldlr−/− mice

Background and aimsAtherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes. By increasing natural antibodies against oxLDL, pneumococcal vaccination has been shown to reduce atherosclerosis in LDL receptor knockout (Ldlr−/−) mice. Relevantly, loss of the lysosomal membrane protein Niemann-Pick Type C1 (NPC1) led to lysosomal accumulation of various lipids and promoted atherosclerosis. Yet, the importance of lysosomal oxLDL accumulation inside macrophages, compared to non-modified LDL, in atherosclerosis has never been established. MethodsBy transplanting NPC1 bone marrow into lethally irradiated Ldlr−/− mice, a hematopoietic mouse model for lysosomal cholesterol accumulation was created. Through injections with heat-inactivated pneumococci, we aimed to demonstrate the specific contribution of lysosomal oxLDL accumulation inside macrophages in atherosclerosis development. ResultsWhile there were no differences in plaque morphology, a reduction in plaque size and plaque inflammation was found in immunized NPC1mut-transplanted mice, compared to non-immunized NPC1mut-transplanted mice. ConclusionsLysosomal oxLDL accumulation within macrophages contributes to murine atherosclerosis. Future intervention strategies should focus specifically on preventing oxLDL, unlike non-modified LDL, from being internalized into lysosomes. Such an intervention can have an additive effect to current existing treatments against atherosclerosis.

Eeffcts of hypertension on Intima-Media Thickness (IMT); application to a human carotid artery

A vast number of deaths in the world have been attributed to atherosclerosis. The prominent aim of this study is proposing an accurate and simple model to investigate the process of arterial wall thickening. In order to investigate LDL (Low Density Lipoprotein) accumulation in arterial wall, a four layer model for arterial wall consisting of endothelium, intima, IEL, and media is presented. All layers are treated as homogenous porous media. This model has been solved both numerically and analytically. Obtained accumulated LDL in the intima is used to calculate oxidized LDL flux. Also, the presented model and clinical data are used to prepare the growth model for arterial wall. Furthermore, the e ect of hypertension on ltration velocity and rate of wall thickening has been studied which is in consistent with experimental data. Results show that the average rates of intima thickening of hypertensive patients with 120 mmHg and 160 mmHg transmural pressure are 5.87 m/year and 6.12 m/year, respectively. This rate for healthy subjects with 70 mmHg transmural pressure has been calculated 4.5 m/year. Finally, this model is applied to a carotid artery, and the maximum intimal growth rate for people with 70 mmHg, 120 mmHg and 160 mmHg transmural pressure is calculated 4.68 m/year, 6.28 m/year, and 6.67 m/year, respectively.

Natural History of Carotid Atherosclerosis in Relation to the Hemodynamic Environment.

Carotid atherosclerosis may lead to devastating clinical outcomes such as stroke. Data on the value of local factors in predicting progression in carotid atherosclerosis are limited. Our aim was to investigate the association of local endothelial shear stress (ESS) and low-density lipoprotein (LDL) accumulation with the natural history of atherosclerotic disease using a series of 3 time points of human magnetic resonance data. Three-dimensional lumen/wall reconstruction was performed in 12 carotids, and blood flow and LDL mass transport modeling were performed. Our results showed that an increase in plaque thickness and a decrease in lumen size were associated with low ESS and high LDL accumulation in the arterial wall. Low ESS (odds ratio [OR]: 2.99; 95% confidence interval [CI]: 2.31-3.88; P < .001 vs higher ESS) and high LDL concentration (OR: 3.26; 95% CI: 2.44-4.36; P < .001 vs higher LDL concentration) were significantly associated with substantial local plaque growth. Low ESS and high LDL accumulation both presented a diagnostic accuracy of 67% for predicting plaque growth regions. Modeling of blood flow and LDL mass transport show promise in predicting progression of carotid atherosclerosis.

Virtual exploration of early stage atherosclerosis.

Biological mechanisms contributing to atherogenesis are multiple and complex. The early stage of atherosclerosis (AS) is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells (FC). To address the difficulty to explore the dynamics of interactions that controls this process, this study aimed to develop a model of agents and infer on the most influential cell- and molecule-related parameters. FC started to accumulate after six to eight months of simulated hypercholesterolemia. A sensitivity analysis revealed the strong influence of LDL oxidation rate on the risk of FC creation, which was exploited to model the antioxidant effect of statins. Combined with an empirical simulation of the drug ability to decrease the level of LDL, the virtual statins treatment led to reductions of oxidized LDL levels similar to reductions measured in vivo. An Open source software was used to develop the agent-based model of early AS. Two different concentrations of LDL agents were imposed in the intima layer to simulate healthy and hypercholesterolemia groups of 'virtual patients'. The interactions programmed between molecules and cells were based on experiments and models reported in the literature. A factorial sensitivity analysis explored the respective effects of the less documented model parameters as (i) agent migration speed, (ii) LDL oxidation rate and (iii) concentration of autoantibody agents. Finally, the response of the model to known perturbations was assessed by introducing statins agents, able to reduce the oxidation rate of LDL agents and the LDL boundary concentrations. jerome.noailly@upf.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Analysis of non-Newtonian effects on Low-Density Lipoprotein accumulation in an artery

In this work, non-Newtonian effects on Low-Density Lipoprotein (LDL) transport across an artery are analyzed with a multi-layer model. Four rheological models (Carreau, Carreau–Yasuda, power-law and Newtonian) are used for the blood flow through the lumen. For the non-Newtonian cases, the arterial wall is modeled with a generalized momentum equation. Convection–diffusion equation is used for the LDL transport through the lumen, while Staverman–Kedem–Katchalsky, combined with porous media equations, are used for the LDL transport through the wall. Results are presented in terms of filtration velocity, Wall Shear Stresses (WSS) and concentration profiles. It is shown that non-Newtonian effects on mass transport are negligible for a healthy intramural pressure value. Non-Newtonian effects increase slightly with intramural pressure, but Newtonian assumption can still be considered reliable. Effects of arterial size are also analyzed, showing that Newtonian assumption can be considered valid for both medium and large arteries, in predicting LDL deposition. Finally, non-Newtonian effects are also analyzed for an aorta–common iliac bifurcation, showing that Newtonian assumption is valid for mass transport at low Reynolds numbers. At a high Reynolds number, it has been shown that a non-Newtonian fluid model can have more impact due to the presence of flow recirculation.

Non-Newtonian effects of blood on LDL transport inside the arterial lumen and across multi-layered arterial wall with and without stenosis

Blood non-Newtonian behavior on low-density lipoproteins (LDL) accumulation is analyzed numerically, while fluid-multilayered arteries are adopted for nonstenotic and 30%–60% symmetrical stenosed models. Present model considers non-Newtonian effects inside the lumen and within arterial layers simultaneously, which has not been examined in previous studies. Navier–Stokes equations are solved along with the mass transport convection–diffusion equations and Darcy’s model for species transport inside the luminal flow and across wall layers, respectively. Carreau model for the luminal flow and the modified Darcy equation for the power-law fluid within arterial layers are employed to model blood rheological characteristics, appropriately. Results indicate that in large arteries with relatively high Reynolds number Newtonian model estimates LDL concentration patterns well enough, however, this model seriously incompetent for regions with low WSS. Moreover, Newtonian model for plasma underestimates LDL concentration especially on luminal surface and across arterial wall. Therefore, applying non-Newtonian model seems essential for reaching to a more accurate estimation of LDL distribution in the artery. Finally, blood flow inside constricted arteries demonstrates that LDL concentration patterns along the stenoses inside the luminal flow and across arterial layers are strongly influenced as compared to the nonstenotic arteries. Additionally, among four stenosis severity grades, 40% stenosis is prone to more LDL accumulation along the post-stenotic regions.

Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque.

Evolution of plaque that is prone to rupture is characterized by inflammation and physical changes. Accumulation of low-density lipoprotein in the sub-intima provides esterified cholesterol (ESC) to macrophages and smooth muscle cells that convert it into free cholesterol (FRC) by cholesteryl ester hydrolases (CEHs). Membrane-bound cholesterol carriers transport FRC to high-density lipoprotein (HDL). Impaired HDL transport function and altered composition can lead to extracellular accumulation of FRC, whereas impaired membrane carrier activity can lead to intracellular FRC accumulation. Saturation of FRC can result in cholesterol crystallization with cell death and intimal injury. Disequilibrium between ESC and FRC can impact foam cell and cholesterol crystal (CC) formation. Cholesterol crystals initiate inflammation via NLRP3 inflammasome leading to interleukin-1β (IL-1β) production inducing C-reactive protein. Eventually, crystals growing from within the plaque and associated inflammation destabilize the plaque. Thus, inhibition of inflammation by antagonists to IL-1β or agents that dissolve or prevent CC formation may stabilize vulnerable plaques.

Analysis of flow and LDL concentration polarization in siphon of internal carotid artery: Non-Newtonian effects

Carotid siphon is known as one of the risky sites among the human intracranial arteries, which is prone to formation of atherosclerotic lesions. Indeed, scientists believe that accumulation of low density lipoprotein (LDL) inside the lumen is the major cause of atherosclerosis. To this aim, three types of internal carotid artery (ICA) siphon have been constructed to examine variations of hemodynamic parameters in different regions of the arteries. Providing real physiological conditions, blood considered as non-Newtonian fluid and real velocity and pressure waveforms have been employed as flow boundary conditions. Moreover, to have a better estimation of risky sites, the accumulation of LDL particles has been considered, which has been usually ignored in previous relevant studies. Governing equations have been discretized and solved via open source OpenFOAM software. A new solver has been built to meet essential parameters related to the flow and mass transfer phenomena. In contrast to the common belief regarding negligible effect of blood non-Newtonian behavior inside large arteries, current study suggests that the non-Newtonian blood behavior is notable, especially on the velocity field of the U-type model. In addition, it is concluded that neglecting non-Newtonian effects underestimates the LDL accumulation up to 3% in the U-type model at the inner side of both its bends. However, in the V and C type models, non-Newtonian effects become relatively small. Results also emphasize that the outer part of the second bend at the downstream is also at risk similar to the inner part of the carotid bends. Furthermore, from findings it can be implied that the risky sites strongly depend on the ICA shape since the extension of the risky sites are relatively larger for the V-type model, while the LDL concentrations are higher for the C-type model.

Low-density lipoprotein accumulation within a carotid artery with multilayer elastic porous wall: fluid–structure interaction and non-Newtonian considerations

Low-density lipoprotein (LDL), which is recognized as bad cholesterol, typically has been regarded as a main cause of atherosclerosis. LDL infiltration across arterial wall and subsequent formation of Ox-LDL could lead to atherogenesis. In the present study, combined effects of non-Newtonian fluid behavior and fluid–structure interaction (FSI) on LDL mass transfer inside an artery and through its multilayer arterial wall are examined numerically. Navier–Stokes equations for the blood flow inside the lumen and modified Darcy’s model for the power-law fluid through the porous arterial wall are coupled with the equations of mass transfer to describe LDL distributions in various segments of the artery. In addition, the arterial wall is considered as a heterogeneous permeable elastic medium. Thus, elastodynamics equation is invoked to examine effects of different wall elasticity on LDL distribution in the artery. Findings suggest that non-Newtonian behavior of filtrated plasma within the wall enhances LDL accumulation meaningfully. Moreover, results demonstrate that at high blood pressure and due to the wall elasticity, endothelium pores expand, which cause significant variations on endothelium physiological properties in a way that lead to higher LDL accumulation. Additionally, results describe that under hypertension, by increasing angular strain, endothelial junctions especially at leaky sites expand more dramatic for the high elastic model, which in turn causes higher LDL accumulation across the intima layer and elevates atherogenesis risk.

Oxidized low-density lipoprotein is a common risk factor for cardiovascular diseases and gastroenterological cancers via epigenomical regulation of microRNA-210.

Hyperlipidemia, including the oxidized low-density lipoprotein (oxLDL) accumulation, is a risk and highly associated with the development of cancers and cardiovascular diseases. microRNA-210 (miR-210), a hypoxia-responsive microRNA regulated by HIF-1α, has been implicated in cancer and cardiovascular disease formation. Furthermore, Bioinformatics analysis revealed that the promoter of the miR-210 gene contains CpG-rich regions. It is unclear whether miR-210 expression could be epigenetically regulated in these disease progresses. The study aimed to explore the relationships between lipid and miR-210 in the context of cardiovascular disease and gastrointestinal cancer. We demonstrated oxLDL can decrease methylation in the miR-210 promoter to up-regulate miR-210. HIF-1α can bind to miR-210 promoter, but this HIF-1α binding site can be blocked by methylation. We showed that subjects of carotid atherosclerosis, stroke patients and cancer patients had hypomethylation in the miR-210 promoter, especially the HIF-1α binding site. Furthermore, miR-210 can directly inhibit sprouty-related EVH1 domain 2 (SPRED2) expressions, and SPRED2 reduces cell migration via ERK/c-Fos/MMPs pathways. Increased miR-210 and reduced SPRED2 levels were found in aorta of mice under high-fat diet and tumor tissues, which implied that miR-210 can be an underlying mechanism to explain oxLDL as a common risk factor for cardiovascular disease and gastrointestinal cancer.

Image-based computational simulation of sub-endothelial LDL accumulation in a human right coronary artery

Accumulation of low density lipoproteins (LDL) in the vessel wall is suggested as the initiator of atherosclerosis and coronary stenosis. This process is associated with the performance of endothelium layer that regulates entering of macromolecules to the vessel wall. Therefore, the present study aims to investigate sub-endothelial accumulation of LDL molecules in a coronary tree and predict atherosclerosis prone sites. Non-Newtonian blood flow is simulated for normal and hypertensive conditions through the lumen of a right coronary artery reconstructed from computed tomography (CT) images. A three-pore model is implemented as the endothelium boundary condition and hence, plasma flow and LDL transport are simulated within the arterial wall. Based on the pore model, endothelium pathways divide into normal junctions, vesicles and leaky junctions. Most of LDL molecules pass through the leaky junctions that arise at locations with low wall shear stress (WSS). Results indicate that increase in the number of leaky junctions at branch points with low WSS can lead to both elevated levels of sub-endothelial LDL accumulation and atherosclerosis risk. Findings reveal that at the branch points with disturbed flow, sub-endothelial concentration of LDL for the hypertensive condition is higher than the normal condition, however for the rest of regions with uniform geometry and unidirectional flow, this is reversed. Comparisons of non-Newtonian and Newtonian flows show mean increases of 34% and 13% in the sub-endothelial concentrations of Newtonian flows during the normal and hypertensive conditions, respectively.

Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice.

Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of low-density lipoprotein in the artery, leading to maladaptive response of cells from the immune system and vessel wall. Strong evidence implicates indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway of tryptophan (Trp) degradation, with immune regulation and anti-inflammatory mechanisms in different diseases. However, the role of IDO and the endogenous degradation of Trp have never been directly examined in atherosclerosis development. We used the IDO inhibitor 1-methyl-Trp (1-MT) to determine the role of IDO-mediated Trp metabolism in vascular inflammation and atherosclerosis. Apoe(-/-) mice were treated with 1-MT in drinking water for 8 weeks. Systemic IDO inhibition led to a significant increase in atherosclerotic lesions that were ∼58 and 54% larger in the aortic arch and root, respectively. 1-MT treatment enhanced vascular inflammation, up-regulated VCAM-1 and CCL2, and increased CD68 macrophage accumulation into the plaque. Notably, the rise in VCAM-1 expression was not limited to the plaque but also found in smooth muscle cells (SMCs) of the tunica media. Furthermore, we found that IDO-dependent Trp metabolism by SMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp metabolite 3-hydroxyanthranilic acid (3-HAA). IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe(-/-) mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis.

Mass transport of low density lipoprotein in reconstructed hemodynamic environments of human carotid arteries: the role of volume and solute flux through the endothelium.

The accumulation of low density lipoprotein (LDL) in the arterial intima is a critical step in the initiation and progression of atheromatous lesions. In this study we examine subject-specific LDL transport into the intima of carotid bifurcations in three human subjects using a three-pore model for LDL mass transfer. Subject-specific carotid artery computational models were derived using magnetic resonance imaging (MRI) to obtain the geometry and phase-contract MRI (PC-MRI) to acquire pulsatile inflow and outflow boundary conditions for each subject. The subjects were selected to represent a wide range of anatomical configurations and different stages of atherosclerotic development from mild to moderate intimal thickening. A fluid-solid interaction (FSI) model was implemented in the computational fluid dynamics (CFD) approach in order to consider the effects of a compliant vessel on wall shear stress (WSS). The WSS-dependent response of the endothelium to LDL mass transfer was modeled by multiple pathways to include the contributions of leaky junctions, normal junctions, and transcytosis to LDL solute and plasma volume flux from the lumen into the intima. Time averaged WSS (TAWSS) over the cardiac cycle was computed to represent the spatial WSS distribution, and wall thickness (WTH) was determined from black blood MRI (BBMRI) so as to visualize intimal thickening patterns in the bifurcations. The regions which are exposed to low TAWSS correspond to elevated WTH and higher mass and volume flux via the leaky junctions. In all subjects, the maximum LDL solute flux was observed to be immediately downstream of the stenosis, supporting observations that existing atherosclerotic lesions tend to progress in the downstream direction of the stenosis.

Quercetin Alleviates High-Fat Diet-Induced Oxidized Low-Density Lipoprotein Accumulation in the Liver: Implication for Autophagy Regulation.

A growing body of evidence has indicated that high-fat diet-induced nonalcoholic fatty liver disease is usually accompanied by oxidized low-density lipoprotein (ox-LDL) deposited in the liver. The current study aimed to investigate the effect of quercetin on high-fat diet-induced ox-LDL accumulation in the liver and to explore the potential underlying mechanisms. The results demonstrate that quercetin supplementation for 24 weeks significantly alleviated high-fat diet-induced liver damage and reduced hepatic cholesterol and ox-LDL level. Quercetin notably inhibited both mRNA and protein expression of CD36 (reduced by 53% and 71%, resp.) and MSR1 (reduced by 25% and 45%, resp.), which were upregulated by high-fat diet. The expression of LC3II was upregulated by 2.4 times whereas that of p62 and mTOR was downregulated by 57% and 63% by quercetin treatment. Therefore, the significantly improved autophagy lysosomal degradation capacity for ox-LDL may be implicated in the hepatoprotective effect of quercetin; scavenger receptors mediated ox-LDL uptake might also be involved.

Analysis of Low Density Lipoprotein (LDL) Transport Within a Curved Artery.

To elucidate the mechanism of the effect of LDL concentration on the thickening of intima in a curved artery, LDL transport in each layer of the curved arterial wall is studied analytically. A comprehensive concentration distribution expression of LDL in each layer of the curved artery wall is presented along with the characterization and estimation of the effect of curvature on the growth of atherosclerosis within the arterial wall. The effect of curvature on species concentration distribution is analyzed and the results are thoroughly benchmarked against prior pertinent works. The concentration at the interface of lumen and endothelium will directly affect the concentration profile inside the arterial wall layers. The results show that the average concentration in the circumferential direction is actually decreasing in the axial direction for a curved artery compared with a straight artery. Small radius ratio and Reynolds number will augment the LDL accumulation at the lumen endothelium interface. The increase in concentration at the lumen/endothelium interface in the axial direction has a minor effect on the concentration profile at the other wall interface layers.

Effects of External and Internal Hyperthermia on LDL Transport and Accumulation Within an Arterial Wall in the Presence of a Stenosis.

Effects of hyperthermia on transport of low-density lipoprotein (LDL) through a stenosed arterial wall are analyzed comprehensively in the present work. The realistic and pertinent aspects of an arterial wall is represented by a multi-layer model, with a proper representation of the thickened intima region due to the atherosclerotic plaque formation. Effects of external and internal hyperthermia on LDL concentration levels are established along with the range of influence of these effects. Various modules of the current work are comprehensively compared with pertinent literature and are found to be in excellent agreement. The effects of external and internal hyperthermia as well as the load level and the axial location of the plaque formation on LDL transport and accumulation for a stenosed artery are established in this work.

Numerical simulation of LDL transport through the carotid arterial wall

Progression of atherosclerosis is related to the accumulation of low density lipoprotein (LDL) in the subendothelial tissue. Approaches to describe this phenomenon include constitutive tissue model...

Enhanced accumulation of LDLs within the venous graft wall induced by elevated filtration rate may account for its accelerated atherogenesis

ObjectiveTo test the hypothesis that the venous graft when implanted in an arterial bypass might endure a significantly elevated water filtration rate, leading to fast infiltration/accumulation of low-density lipoproteins (LDLs) within the graft wall and hence the accelerated atherogenesis. MethodsWe measured filtration rates of the swine femoral artery and lateral saphenous vein under venous and arterial hemodynamic conditions in vitro. Based on the measured filtration rates, we numerically simulated LDL transport in an arterial bypass model with a venous graft. Moreover, in order to validate the theoretical prediction, we measured DiI-LDLs uptake by both arteries and veins under arterial condition. ResultsThe experimental results showed that when subjected to arterial hemodynamic condition, the filtration rate of the venous wall was increased sharply, and significantly higher than that of the artery. Moreover, different from the hydraulic conductivity of artery, the venous one would increase with increasing pressure. The numerical results showed that for the venous graft, both luminal surface LDL concentration and LDL accumulation within the vessel wall were significantly higher than those for the host artery. In addition, the experiment, which was used to confirm theoretical prediction, showed that the amount of DiI-LDLs uptake by the venous wall was much higher compared with arterial wall. ConclusionThe present study suggests that the accelerated atherogenesis of the venous graft is attributable to its elevated filtration rate that may lead to both aggravated concentration polarization of LDLs and enhanced convective transport of LDLs into the graft wall.

In vitro oxidation of LDL by ozone

Recent studies suggest that ozone is present in atherosclerotic lesions. Since these lesions are characterized by a dramatic accumulation of low-density lipoprotein (LDL), we aimed to investigate whether ozone is capable of oxidizing LDL, thereby rendering this lipoprotein atherogenic. Lipid hydroperoxide (LPO) concentrations and thiobarbituric acid reactive substances (TBARS) were measured to assess the oxidative status of the lipid part of LDL. Relative electrophoretic mobility (REM) and oxidation-specific immune epitopes were measured to assess the oxidative status of the protein part (apoB) of the LDL particle. Ozone turned out to be a potent oxidant of LDL. LPO concentrations, TBARS, REM, and oxidation-specific immune epitopes significantly increased upon ozonization. Our results suggest that ozonization of LDL may be a novel pathway which supports atherogenesis. Ozone is capable of oxidizing the lipid part of LDL, followed by immediate oxidation of the protein part of LDL, rendering the lipoprotein atherogenic.

Lp(a)/apo(a) Modulate MMP-9 Activation and Neutrophil Cytokines in Vivo in Inflammation to Regulate Leukocyte Recruitment

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.