In Vivo Arterial Lipoprotein Lipase Expression Augments Inflammatory Responses and Impairs Vascular Dilatation

Abstract

Objective-Although epidemiologic data suggest that hypertriglyceridemia and elevated plasma levels of fatty acids are toxic to arteries, in vitro correlates have been inconsistent. To investigate whether increased endothelial cell expression of lipoprotein lipase (LpL), the primary enzyme creating free fatty acids from circulating triglycerides (TG), affects vascular function, we created transgenic mice that express human LpL (hLpL) driven by the promoter and enhancer of the Tie2 receptor. Methods and Results-Mice expressing this transgene, denoted EC-hLpL and L for low and H for high expression, had decreased plasma TG levels compared with wild-type mice (WT): 106Ϯ31 in WT, 37Ϯ17 (line H), and 63Ϯ31 mg/dL (line L) because of a reduction in VLDL TG; plasma cholesterol and HDL levels were unaltered. Crossing a high expressing EC-hLpL transgene onto the LpL knockout background allowed for survival of the pups; TG in these mice was approximately equal to that of heterozygous LpL knockout mice. Surprisingly, under control conditions the EC-hLpL transgene did not alter arterial function or endothelial cell gene expression; however, after tumor necrosis factor (TNF)-␣ treatment, arterial vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and endogenous TNF-␣ mRNA levels were increased and arteries had impaired endothelium-dependent vasodilatation. This was associated with reduced eNOS dimers. Conclusions-Therefore, we hypothesize that excess vascular wall LpL augments vascular dysfunction in the setting of inflammation. LpL is the rate-limiting enzyme for hydrolysis of plasma TG. LpL is synthesized by myocytes and adipocytes but is thought to function primarily on the luminal surface of endothelial cells. Therefore, along the arterial wall much of the exposure of endothelial cells to FAs is modulated by LpL actions.LpL has been suggested to have a dual effect on atherosclerosis development. 6 We and others have demonstrated that LpL contributes to lipid accumulation by stimulating the cellular binding and uptake of atherogenic lipoproteins in different vascular cell types including smooth muscle cells and macrophages. 7,8 Moreover, loss of macrophage LpL reduces atherosclerosis. 9 LpL acts as an activator of macrophage function, inducing TNF alpha (TNF-␣), 10 augmenting monocyte adhesion 11,12 and increasing phagocytosis in low glucose conditions. 13 Although these data suggest that LpL has atherogenic and inflammatory effects, there are contradictory data. LpL is reported to play an antiinflammatory role through generation of PPAR ligands for endothelial cells 14 and macrophages. 15 In human endothelial cells, LpL alone attenuated the inflammatory cascade produced by TNF-␣. 16 Thus, the function and role of LpL in inflammatory responses are not clear, but may vary depending on the in vitro conditions studied.To study the actions of LpL in arteries, we created mice with human LpL (hLpL) expression specifically in endothelial cells using the Tie2 promoter-enhancer 17 to drive an hLpL minigene. These transgenic mic...

The GPIHBP1–LPL Complex Is Responsible for the Margination of Triglyceride-Rich Lipoproteins in Capillaries

“…In a second approach, we measured TRL margination in mice that express human LPL in endothelial cells [EC-hLPLH transgenic mice; (Takahashi et al, 2008)]. LPL is normally produced by myocytes in the heart and requires GPIHBP1 to move it across endothelial cells to the capillary lumen.…”

The vascular contribution to Alzheimer's disease

“…Additional experiments using TEER (transendothelial electrical resistance) measurements showed that the resistance of the monolayer decreased following treatment with TGRL lipolysis products [166]. Recent studies in mice overexpressing hLpL (human LpL) have shown that excess vascular wall LpL augments vascular dysfunction in the setting of inflammation [176,177]. Furthermore, in transgenic mice expressing hLpL, agonist-induced contraction of smooth muscle cells was increased when compared with that of wild-type mice [178].…”

Impact of circulating esterified eicosanoids and other oxylipins on endothelial function

“…Although the relative abundance of the HODEs was low and their potency was similar to that of their parent FAs, this study established that LpL lipolysate effects on endothelial cells were dependent on the released milieu of FAs, which included an array of oxylipins. TNF-α-induced infl ammation normally reduces LpL expression on the endothelium; however, when LpL is maintained, increased vascular cell adhesion molecule (VCAM) and E-selectin expression and impaired endothelium-dependent vasodilation are observed [39]. Coleman et al [40] demonstrated an LpL-dependent role for Cu 2+ -oxidized VLDL in activating adipocytes via PPARβ/δ, and simultaneously demonstrated the activation of PPARβ/δ by 13-HODE and 15-HETE.…”