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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:455.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

Mayumi Takahashi; Yaeko Hiyama; Masayoshi Yokoyama; Shuiqing Yu; Yunying Hu; Kristan Melford; André Bensadoun; Ira J. Goldberg

From the Department of Medicine (M.T., Y.H., M.Y., S.Y., Y.H., I.J.G.), Columbia University College of Physicians & Surgeons, New York; Division of Nutritional Sciences (K.M., A.B.), Cornell University, Ithaca, NY.

Correspondence to Ira J. Goldberg, Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail ijg3{at}columbia.edu

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): 106±31 in WT, 37±17 (line H), and 63±31 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.

Expressing human lipoprotein lipase (LpL) in endothelial cells allows for survival of LpL knockout mice. Although under control conditions, expression of this transgene did not alter inflammatory gene expression in arteries, after TNF- treatment there was greater expression of inflammatory molecules and reduced arterial vasodilatation.

Key Words: triglyceride • fatty acids • lipolysis • adhesion molecules • endothelial cells