Lipoprotein lipase-mediated lipolysis of very low density lipoproteins increases monocyte adhesion to aortic endothelial cells

Uday, Suma; Kulkarni, Nita M.; Ferguson, E.; Newton, Roger S.

doi:10.1016/0006-291x(92)90267-o

Cited by 36 publications

(17 citation statements)

References 10 publications

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“…LPL promotes lipoprotein internalization and lipid accumulation by macrophages through local lipolysis and bridging of lipoproteins (43,(52)(53)(54). In addition, localized production of LPL by macrophages within the arterial wall has been shown to promote foam cell and lesion formation (31), enhance monocyte recruitment and retention in the vessel wall (31,(55)(56)(57), and increase retention of lipoproteins in the extracellular matrix through LPLmediated bridging of lipoproteins (58)(59)(60). All of these processes enhance aortic atherosclerosis by promoting foam cell formation.…”

Section: Discussionmentioning

confidence: 99%

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Zhang¹,

González-Navarro²,

Amar³

et al. 2003

J. Clin. Invest.

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Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO × HL-KO mice, as well as LCAT-Tg and LCAT-Tg × HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.

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Section: Discussionmentioning

confidence: 99%

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Zhang¹,

González-Navarro²,

Amar³

et al. 2003

J. Clin. Invest.

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“…Non-apoE-containing lipoproteins have relatively weak affinity for proteoglycans in physiological ionic conditions. This has led us (28,29) and others (30) to suggest that lipoprotein-proteoglycan interaction requires an intermediary molecule such as lipoprotein lipase. The other lipoprotein-associating molecule that would be expected to increase lipoprotein-proteoglycan interaction, apoE, is antiatherosclerotic.…”

Section: Downloaded Frommentioning

confidence: 99%

Atherosclerosis in perlecan heterozygous mice

Vikramadithyan

Kako

Chen

et al. 2004

Journal of Lipid Research

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The hypothesis that lipoprotein association with perlecan is atherogenic was tested by studying atherosclerosis in mice that had a heterozygous deletion of perlecan, the primary extracellular heparan sulfate proteoglycan in arteries. We first studied the expression of perlecan in mouse lesions and noted that this proteoglycan in aorta was found in the subendothelial matrix. Perlecan was also a major component of the lesional extracellular matrix. Mice with a heterozygous deletion had a reduction in arterial wall perlecan expression. Atherosclerosis in these mice was studied after crossing the defect into the apolipoprotein E (apoE) and LDL receptor knockout backgrounds. At 12 weeks, chowfed apoE null mice with a heterozygous deletion had less atherosclerosis. However, at 24 weeks and in the LDL receptor heterozygous background, the presence of a perlecan knockout allele did not significantly alter lesion size. Thus, it appears that loss of perlecan leads to less atherosclerosis in early lesions. Although this might be attributable to a decrease in lipoprotein retention, it should be noted that perlecan might mediate multiple other processes that could, in sum, accelerate atherosclerosis. Much of atherosclerosis research in the 20th century focused on the cholesterol hypothesis. The evidence that plasma cholesterol-containing lipoproteins cause atherosclerosis is indisputable. However, as was nicely summarized nearly 50 years ago (1), how these lipid-containing particles accumulate within the artery and then produce inflammatory reactions is still unclear. A refinement to the "infiltrative theory" has been an attempt to define the biochemical interactions that lead to this process. Because the lipoproteins are initially found in the extracellular space, they are thought to bind to protein or carbohydrate components of the extracellular matrix. Among the molecules that have been most studied in this respect are proteoglycans (2).Within the artery are a number of classes of proteoglycans, complex proteins that contain highly negatively charged carbohydrates. There are several observations that support the proteoglycan-lipoprotein association hypothesis. 1 ) Dermatan/chondroitin sulfate proteoglycans are found in greater amounts in lesions (3, 4), and some classes of these proteins are found in regions that also contain apolipoprotein B (apoB) (5), the major protein component of LDL and remnant lipoproteins. 2 ) Complexes of proteoglycans and LDL have been isolated from arteries (6). 3 ) Prolonged incubations of proteoglycans and LDL will, in vitro, produce aggregates (7).Of all the proteoglycans, the most heavily charged and most avid LDL binding are the heparan sulfate proteoglycans (8). Heparin, a highly charged carbohydrate of this class, has been studied because it interacts with apoB-containing lipoproteins (9, 10). This reaction, however, is most evident in low ionic strength solutions; in several reports, the proteoglycan-LDL complexes are dissociated by physiologic saline (9). Moreover, increasing ...

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“…On the basis primarily of in vitro studies, a number of functions of LPL expression by the macrophage have been proposed to promote foam cell formation and atherosclerosis. LPL increases monocyte adhesion to aortic endothelial cells, and LPL can function as a monocyte adhesion protein (13). Thus, macrophage LPL may promote macrophage recruitment to and retention in the vessel wall.…”

Section: Introductionmentioning

confidence: 99%

Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo

Babaev¹,

Fazio²,

Gleaves³

et al. 1999

J. Clin. Invest.

215

176

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Expression of lipoprotein lipase (LPL) by the macrophage has been proposed to promote foam cell formation and atherosclerosis, primarily on the basis of in vitro studies. LPL-deficient mice might provide a model for testing the role of LPL secretion by the macrophage in an in vivo system. Unfortunately, homozygous deficiency of LPL in the mouse is lethal shortly after birth. Because the fetal liver is the major site of hematopoiesis in the developing fetus, transplantation of C57BL/6 mice with LPL -/-fetal liver cells (FLCs) was used to investigate the physiologic role of macrophage LPL expression in vivo. Thirty-four female C57BL/6 mice were lethally irradiated and reconstituted with FLCs from day 14 LPL +/+ , LPL +/-, and LPL -/-donors. No significant differences were detected in plasma levels of post-heparin LPL activity or in serum cholesterol or triglyceride levels between the 3 groups on either a chow diet or an atherogenic diet. After 19 weeks on the atherogenic diet, aortae were collected for quantitative analysis of the extent of aortic atherosclerosis. LPL expression was detected by immunocytochemistry and in situ hybridization in macrophages of aortic atherosclerotic lesions of LPL +/+ →C57BL/6 and LPL +/-→C57BL/6 mice, but not in LPL -/-→C57BL/6 mice, whereas myocardial cells expressed LPL in all groups. The mean aortic lesion area was reduced by 55% in LPL -/-→C57BL/6 mice compared with LPL +/+ →C57BL/6 mice and by 45% compared with LPL +/-→C57BL/6 mice, respectively. These data demonstrate in vivo that LPL expression by macrophages in the artery wall promotes foam cell formation and atherosclerosis.

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Lipoprotein lipase-mediated lipolysis of very low density lipoproteins increases monocyte adhesion to aortic endothelial cells

Cited by 36 publications

References 10 publications

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Atherosclerosis in perlecan heterozygous mice

Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo

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