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.