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(Circulation Research. 2007;101:777.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse

Evidence for a Role of Lipoprotein Lipase

Maria Gustafsson, Malin Levin, Kristina Skålén, Jeanna Perman, Vincent Fridén, Pernilla Jirholt, Sven-Olof Olofsson, Sergio Fazio, MacRae F. Linton, Clay F. Semenkovich, Gunilla Olivecrona, Jan Borén

From the Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine (M.G., M.L., K.S., J.P., V.F., P.J., S.-O.O., J.B.), Göteborg University, Sweden; Division of Cardiovascular Medicine (S.F., M.F.L.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Medicine (C.F.S.), Washington University, St Louis, Mo; and Department of Medical Biosciences (G.O.), Umeå University, Sweden.

Correspondence to Jan Borén, MD, PhD, Wallenberg Laboratory, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail Jan.Boren{at}wlab.gu.se

Direct binding of apolipoprotein (apo)B-containing lipoproteins to proteoglycans is the initiating event in atherosclerosis, but the processes involved at later stages of development are unclear. Here, we investigated the importance of the apoB–proteoglycan interaction in the development of atherosclerosis over time and investigated the role of lipoprotein lipase (LPL) to facilitate low-density lipoprotein (LDL) retention at later stages of development. Atherosclerosis was analyzed in apoB transgenic mice expressing LDL with normal (control LDL) or reduced proteoglycan-binding (RK3359-3369SA LDL) activity after an atherogenic diet for 0 to 40 weeks. The initiation of atherosclerosis was delayed in mice expressing RK3359-3369SA LDL, but they eventually developed the same level of atherosclerosis as mice expressing control LDL. Retention studies in vivo showed that although higher levels of ¹³¹I-tyramine cellobiose–labeled control LDL (¹³¹I-TC-LDL) were retained in nonatherosclerotic aortae compared with RK3359-3369SA ¹³¹I-TC-LDL, the retention was significantly higher and there was no difference between the groups in atherosclerotic aortae. Lower levels of control ¹²⁵I-TC-LDL and RK3359-3369SA ¹²⁵I-TC-LDL were retained in atherosclerotic aortae from ldlr^–/– mice transplanted with lpl^–/– compared with lpl^+/+ bone marrow. Uptake of control LDL or RK3359-3369SA LDL into macrophages with specific expression of human catalytically active or inactive LPL was increased compared with control macrophages. Furthermore, transgenic mice expressing catalytically active or inactive LPL developed the same extent of atherosclerosis. Thus, retention of LDL in the artery wall is initiated by direct LDL–proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL.

Key Words: apolipoprotein B • low-density lipoproteins • retention • atherosclerosis • lipoprotein lipase

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