Endothelial Lipase Modulates Susceptibility to Atherosclerosis in Apolipoprotein-E-deficient Mice

Ishida, Tatsuro; Choi, S.; Kundu, Ramendra K.; Spin, Joshua M.; Yamashita, Tomoya; Hirata, Ken‐ichi; Kojima, Yoshiyuki; Yokoyama, Mitsuhiro; Cooper, Allen D.; Quertermous, Thomas

doi:10.1074/jbc.m406360200

Cited by 127 publications

(115 citation statements)

References 31 publications

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“…Taken together, EL induction in local and chronic inflammation may contribute to monocyte/macrophage recruitment and lipoprotein accumulation in the vascular wall. Thus, the present data imply that EL may modulate the progression of vascular diseases (36).…”

Section: Discussionmentioning

confidence: 88%

Endothelial Lipase Modulates Monocyte Adhesion to the Vessel Wall

Kojma

Hirata

Ishida

et al. 2004

Journal of Biological Chemistry

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Endothelial lipase (EL), a new member of the lipoprotein lipase gene family, plays a central role in high density lipoprotein metabolism. Previous studies indicated that EL is expressed in endothelial cells, macrophages, and smooth muscle cells in atherosclerotic lesions in human coronary arteries. However, the functional role of EL in the local vessel wall remains obscure. In this study, we evaluated the ability of EL to modulate monocyte adhesion to the endothelial cell surface. EL mRNA and protein levels were markedly increased in tissues of the mouse model of inflammation induced by lipopolysaccharide injection. Adhesion assays in vitro revealed that overexpression of EL in COS7 or Pro5 cells enhanced monocyte bindings to the EL-expression cells. Heparin or heparinase treatment inhibited EL-mediated increases of monocyte adhesion in a dose-dependent manner. Moreover, ex vivo adhesion assays revealed that the number of adherent monocytes on aortic strips was significantly increased in EL transgenic mice and decreased in EL knock-out mice as compared with wildtype mice. These results suggest that EL on the endothelial cell surface can promote monocyte adhesion to the vascular endothelium through the interaction with heparan sulfate proteoglycans. Thus, the up-regulation of EL by inflammatory stimuli may be involved in the progression of inflammation.The lipoprotein lipase gene family plays a crucial role in the lipid metabolism for the regulation of circulating lipoprotein levels and affects the process of atherosclerotic vascular diseases (1-4). The lipoprotein lipase gene family includes lipoprotein lipase (LPL) 1 and hepatic lipase (HL), both of which are synthesized and secreted by non-endothelial cells. We and other groups have reported a new member of the lipase gene family, endothelial lipase (EL). EL is mainly synthesized and secreted by vascular endothelial cells (5, 6). Previous studies have demonstrated that EL showed preferential substrate specificity for high density lipoprotein (HDL) (7). EL knock-out mice (LIPGϪ/Ϫ) showed an elevated plasma HDL-cholesterol (HDL-C) level. In contrast, human EL transgenic mice (hLIPGTg) or overexpression of human EL in mice by adenovirus vectors showed decreased plasma HDL-C and apoA-I levels (6,8). These data suggest that EL is a determinant of HDL levels in mice. In addition to their functional role in lipoprotein metabolism at the endothelial cell surface, lipases possess non-enzymatic functions in the vascular wall. LPL within the vessel wall increases lipoprotein retention within the subendothelial cell matrix (9, 10) and in the aortic segment (11, 12). LPL can also enhance monocyte adhesion to endothelial cells (13,14). The local expression of LPL in the vascular wall has been implicated in the accumulation of lipoproteins and the acceleration of atherosclerosis progression through this bridging function (15). Macrophage-derived LPL in the vessel wall is known to act as a proatherogenic molecule, determining susceptibility to atherosclerotic lesion formation...

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Section: Discussionmentioning

confidence: 88%

Endothelial Lipase Modulates Monocyte Adhesion to the Vessel Wall

Kojma

Hirata

Ishida

et al. 2004

Journal of Biological Chemistry

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“…EL has been shown to be expressed in the macrophages of atherosclerotic lesions in humans and mice 34,35) , and the expression was likely to be regulated during atherosclerotic progression. However, the function of EL in this cell type was not clear.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Lipase is Increased by Inflammation and Promotes LDL Uptake in Macrophages

Yasuda

Hirata

Ishida

et al. 2007

JAT

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Aim: Endothelial lipase (EL) is a member of the lipoprotein lipase family that regulates HDL metabolism. EL is known to act as a bridging molecule for monocytes or lipoproteins in vascular endothelial cells. We investigated the role and regulatory mechanisms of EL expression in macrophages. Methods: Macrophages originating from wild-type (EL / ) and EL-deficient (EL / ) mice were stimulated with lipopolysaccharide (LPS). The expression of EL mRNA was evaluated by northern blotting. DiI-LDL was used to measure the uptake of native low-density lipoprotein (nLDL). Results: LPS increased EL mRNA levels by increasing intracellular oxidative stress in the macrophages. LPS did not affect EL expression in macrophages derived from Toll-like receptor 4 (TLR4) gene mutant mice, C3H/HeJ. The uptake of nLDL after LPS-treatment was significantly lower in macrophages from EL / mice than those from EL / mice. Simvastatin suppressed the LPS-induced upregulation of EL expression and uptake of nLDL. Conclusions: EL expression is upregulated by LPS via TLR4 and promotes the uptake of nLDL by macrophages. Simvastatin inhibits the LPS-induced up-regulation and uptake in macrophages. Thus, our findings provide a novel role for EL in lipoprotein metabolism and would expand the range of anti-atherogenic effects of statins.

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“…Overexpression of EL decreases in HDL cholesterol and apoA-I levels decreased in mice (Ishida, 2003;Jaye, 1999). By contrast, a deficiency of EL increases HDL levels (Ishida, 2003;Ma, 2003), in addition to atherogenic action (Ishida, 2004) and allergic asthma (Otera, 2009). Another study confirmed the high HDL-C levels in EL-/-mice but did not document an association with atherosclerosis (Ko, 2005).…”

Section: Lipolysis Of Apob-containing Lipoproteinsmentioning

confidence: 49%