Retention of atherogenic lipoproteins in atherogenesis

Gustafsson, Maria; Flood, Christofer; Jirholt, Pernilla; Borén, Jan

doi:10.1007/s00018-003-3262-x

Cellular and Molecular Life Sciences (CMLS)

2004

DOI: 10.1007/s00018-003-3262-x

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Retention of atherogenic lipoproteins in atherogenesis

Maria Gustafsson

Christofer Flood

Pernilla Jirholt

et al.

Abstract: Atherosclerosis is a multifactorial disease whose pathogenesis is still unclear. Mounting evidence, however, supports the concept that subendothelial retention of apoB100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation.

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Cited by 20 publications

(18 citation statements)

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“…The key initial step in early atherogenesis is the retention, or trapping, of apoB-lipoproteins within the subendothelium of focal, susceptible regions of the arterial tree 1–3. Retained and modified lipoproteins provoke a series of biologic responses that can explain all subsequent features of early atherogenesis 1,2.…”

mentioning

confidence: 99%

Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression

Devlin

Leventhal²,

Kuriakose³

et al. 2008

ATVB

141

116

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Objective-The key initial step in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Acid sphingomyelinase (acid SMase), an enzyme present extracellularly within the arterial wall, strongly enhances lipoprotein retention in model systems in vitro, and retained lipoproteins in human plaques are enriched in ceramide, a product of SMase. We now sought to test a direct causative role for acid SMase in lipoprotein retention and atherogenesis in vivo. T he key initial step in early atherogenesis is the retention, or trapping, of apoB-lipoproteins within the subendothelium of focal susceptible regions of the arterial tree. [1][2][3] Retained and modified lipoproteins provoke a series of biological responses that can explain all subsequent features of early atherogenesis. 1,2 Lipoprotein retention within prelesional segments initially involves direct binding of positively charged domains on apoB to negatively charged elements of arterial matrix, chiefly proteoglycans. 4,5 In later stages, lipoprotein retention can be enhanced further by size-related trapping of large lipoproteins in the subendothelium and by uptake by subendothelial macrophages (below). Moreover, lesional cells secrete additional molecules, such as sphingomyelinase and lipoprotein lipase, that are proposed to shift the molecular basis for further lipoprotein retention while also substantially accelerating retention and hence lesion progression. Thus, understanding the molecular mechanisms of subendothelial lipoprotein retention in prelesional and then lesional arteries is a critical goal of atherogenesis research.Previous work has suggested a number of factors that can influence subendothelial lipoprotein retention, including (1) the concentration of circulating atherogenic lipoproteins; (2) endothelial permeability; (3) the nature and amounts of proretentive molecules within the subendothelial space, notably proteoglycans and lipoprotein lipase (LpL), which bridges lipoproteins to matrix; and (4) structure and composition of the lipoproteins, which can be altered by enzymatic and nonenzymatic processes within the subendothelial space. [1][2][3] A large number of studies in vitro implicate the secretory form of acid sphingomyelinase (S-SMase) in proretentive modifications of atherogenic lipoproteins. S-SMase arises from the acid SMase (Asm) gene, which also gives rise to lysosomal acid SMase. 6 S-SMase is secreted by cell types Correlative support for a role of S-SMase in atherogenesis per se has been provided by several human and animal atherosclerosis studies. For example, extracellular acid SMase is present in human and murine atherosclerotic lesions, 16 and aggregated lipoproteins extracted from human atheromata are specifically enriched in ceramide, indicating hydrolysis by sphingomyelinase. 12 Moreover, recent work has demonstrated an association between high SM content in circulating lipoproteins, which enhances S-SMase-mediated hydrolysis, and increased risk for aortic atherosclerosis in mice and coronary...

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mentioning

confidence: 99%

Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression

Devlin

Leventhal²,

Kuriakose³

et al. 2008

ATVB

141

116

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“…Key Words: atherosclerosis Ⅲ macrophage Ⅲ apoptosis Ⅲ phagocytosis Ⅲ inflammation O ne of the earliest events in atherosclerosis is the entry of monocytes into focal areas of the arterial subendothelium that have accumulated matrix-retained and often modified lipoproteins. [1][2][3][4][5] The monocytes differentiate into macrophages, and the macrophages accumulate large amounts of intracellular cholesterol through the ingestion of the subendothelial lipoproteins. 1,2,6 -8 The presence of cholesterolloaded macrophages in atherosclerotic lesions is a prominent feature throughout the life of the lesion, and these cells have a tremendous impact on lesion progression.…”

mentioning

confidence: 99%

“…[1][2][3][4][5] The monocytes differentiate into macrophages, and the macrophages accumulate large amounts of intracellular cholesterol through the ingestion of the subendothelial lipoproteins. 1,2,6 -8 The presence of cholesterolloaded macrophages in atherosclerotic lesions is a prominent feature throughout the life of the lesion, and these cells have a tremendous impact on lesion progression.…”

mentioning

confidence: 99%

Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis

Tabas

2005

ATVB

590

535

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Abstract-Macrophage apoptosis occurs throughout all stages of atherosclerosis, yet new findings in vivo suggest that the consequences of this event may be very different in early versus late atherosclerotic lesions. In early lesions, where phagocytic clearance of apoptotic cells appears to be efficient, macrophage apoptosis is associated with diminished lesion cellularity and decreased lesion progression. In late lesions, however, a number of factors may contribute to defective phagocytic clearance of apoptotic macrophages, leading to secondary necrosis of these cells and a proinflammatory response. The cumulative effect of these late lesional events is generation of the necrotic core, which, in concert with proatherogenic effects of residual surviving macrophages, promotes further inflammation, plaque instability, and thrombosis. Thus, the ability or lack thereof of lesional phagocytes to safely clear apoptotic macrophages may be an important determinant of acute atherothrombotic clinical events. Further understanding of the mechanisms involved in macrophage apoptosis and phagocytic clearance might lead to novel therapeutic strategies directed against the progression of advanced plaques. Key Words: atherosclerosis Ⅲ macrophage Ⅲ apoptosis Ⅲ phagocytosis Ⅲ inflammation O ne of the earliest events in atherosclerosis is the entry of monocytes into focal areas of the arterial subendothelium that have accumulated matrix-retained and often modified lipoproteins. [1][2][3][4][5] The monocytes differentiate into macrophages, and the macrophages accumulate large amounts of intracellular cholesterol through the ingestion of the subendothelial lipoproteins. 1,2,6 -8 The presence of cholesterolloaded macrophages in atherosclerotic lesions is a prominent feature throughout the life of the lesion, and these cells have a tremendous impact on lesion progression. 9 -11 Therefore, the number of macrophages in lesions is an important measure of atherosclerotic burden. The processes that determine macrophage cellularity in lesions include two factors that promote the accumulation of these cells-monocyte/macrophage entry and macrophage proliferation-and two features that lead to cell depletion-macrophage death and macrophage egress. [12][13][14][15][16] See coverThis review will address one of these processes, namely, lesional macrophage death. Within this topic, there are many important areas, including evidence that macrophages die in the course of atherosclerosis; inducers and mechanisms of lesional macrophage death; and functional consequences of macrophage death in the setting of atherosclerosis. The first two areas have been covered widely in a number of important articles and comprehensive reviews. 14,17-26 After a brief synopsis and update of these two areas, this review will focus on a hypothesis related to the functional consequences of lesional macrophage death. The hypothesis states that (1) the ultimate effect of macrophage death on plaque progression depends on the lesion stage during which macrophage death occurs; a...

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“…This is the environment where key initial interactions contributing to atherogenesis take place. [12][13][14][15]32 Therefore, it is important to explore whether metabolic alterations associated with IR and T2D can be responsible for the atherogenic changes observed in the human extracellular intima. 7 The present experiments indicate that linoleic and palmitic acid increased the expression of genes for the core proteins of versican, the small leucine-rich PGs with either 1 (decorin) or 2 (biglycan) chondroitin/DS side chains, and perlecan, the main HS-containing PG of the basement membrane.…”

mentioning

confidence: 99%

“…11,12 Retention of low-density lipoprotein (LDL) in the intima by chondroitin sulfate (CS)-rich PGs appears to be a key step in atherogenesis at sites of intima thickening. [13][14][15] We reported that the expression of genes for extracellular matrix proteins and PGs is increased when human arterial SMCs (hASMCs) are exposed to NEFA. Furthermore, the extracellular matrix produced by the NEFA-treated hASMC had a higher affinity for LDL.…”

mentioning

confidence: 99%

Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein

Rodrı́guez-Lee

Östergren‐Lundén

Wallin

et al. 2006

ATVB

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Objective-The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein. Methods and Results-hASMC exposed for 72 hours to high concentrations (800 mol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPAR␥ agonist rosiglitazone (10 mol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity. Key Words: proteoglycans Ⅲ smooth muscle cells Ⅲ LDL Ⅲ fatty acids Ⅲ insulin I nsulin resistance (IR) and type 2 diabetes (T2D) are associated with a 2-to 4-fold increase in atherosclerotic coronary artery disease. 1,2 Changes in circulating lipoproteins, chronic high levels of albumin-bound nonesterified fatty acids (NEFA, and hyperinsulinemia are important contributors to this association. [3][4][5] Atherogenesis involves a tissue response to deposition of apoB lipoproteins and insulin signaling defects that may affect vascular cells. 6 The accelerated intimal thickening of large arteries observed in IR and diabetes includes excessive production of matrix components, such as proteoglycans (PGs) and collagens by smooth muscle cells (SMCs). 7 Cell culture experiments suggest that increased endothelial cell permeability and SMC alterations of matrix production could be caused by exposure to excessive amounts of NEFA. 8 -10 In IR, arterial cells are chronically exposed to increased levels of circulating NEFA. In addition, NEFA could be produced locally by lipolytic degradation of lipoproteins, additionally increasing their concentration in the arterial intima. 11,12 Retention of low-density lipoprotein (LDL) in the intima by chondroitin sulfate (CS)-rich PGs appears to be a key step in atherogenesis at sites of intima thickening. [13][14][15] We reported that the expression of genes for extracellular matrix proteins and PGs is increased when human arterial SMCs (hASMCs) are exposed to NEFA. Furthermore, the extracellular matrix produced by the NEFA-treated hASMC had a higher affinity for LDL. 9 In this study we describe how linoleate (LO) and palmitate (PA) increased the expression of genes encoding the core proteins of the main secreted PGs from hASMC and of the key enzymes in CS-glycosaminoglycan (GAG) biosynthesis. Exposure to LO also altered...

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Retention of atherogenic lipoproteins in atherogenesis

Cited by 20 publications

References 58 publications

Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression

Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression

Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis

Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein

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