BACKGROUND: We previously demonstrated that macrophage low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) deficiency increases atherosclerosis despite antiatherogenic changes including decreased uptake of remnants and increased secretion of apolipoprotein E (apoE). Thus, our objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects. METHODS AND RESULTS: We examined atherosclerosis development in mice with specific deletion of macrophage LRP1 (apoE(-/-) MΦLRP1(-/-)) and in LDLR(-/-) mice reconstituted with apoE(-/-) MΦLRP1(-/-) bone marrow. The combined absence of apoE and LRP1 promoted atherogenesis more than did macrophage apoE deletion alone in both apoE-producing LDLR(-/-) mice (+88%) and apoE(-/-) mice (+163%). The lesions of both mouse models with apoE(-/-) LRP1(-/-) macrophages had increased macrophage content. In vitro, apoE and LRP1 additively inhibit macrophage apoptosis. Furthermore, there was excessive accumulation of apoptotic cells in lesions of both LDLR(-/-) mice (+110%) and apoE(-/-) MΦLRP1(-/-) mice (+252%). The apoptotic cell accumulation was partially due to decreased efferocytosis as the ratio of free to cell-associated apoptotic nuclei was 3.5-fold higher in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Lesion necrosis was also increased (6 fold) in apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Compared with apoE(-/-) mice, the spleens of apoE(-/-) MΦLRP1(-/-) mice contained 1.6- and 2.4-fold more total and Ly6-C(high) monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-C(high) and CC-chemokine receptor 2-positive cells in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice, suggesting that accumulation of apoptotic cells enhances lesion development and macrophage content by promoting the recruitment of inflammatory monocytes. CONCLUSION: Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE involving macrophage apoptosis and monocyte recruitment.
BACKGROUND: We previously demonstrated that macrophage low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) deficiency increases atherosclerosis despite antiatherogenic changes including decreased uptake of remnants and increased secretion of apolipoprotein E (apoE). Thus, our objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects. METHODS AND RESULTS: We examined atherosclerosis development in mice with specific deletion of macrophage LRP1 (apoE(-/-) MΦLRP1(-/-)) and in LDLR(-/-) mice reconstituted with apoE(-/-) MΦLRP1(-/-) bone marrow. The combined absence of apoE and LRP1 promoted atherogenesis more than did macrophage apoE deletion alone in both apoE-producing LDLR(-/-) mice (+88%) and apoE(-/-) mice (+163%). The lesions of both mouse models with apoE(-/-) LRP1(-/-) macrophages had increased macrophage content. In vitro, apoE and LRP1 additively inhibit macrophage apoptosis. Furthermore, there was excessive accumulation of apoptotic cells in lesions of both LDLR(-/-) mice (+110%) and apoE(-/-) MΦLRP1(-/-) mice (+252%). The apoptotic cell accumulation was partially due to decreased efferocytosis as the ratio of free to cell-associated apoptotic nuclei was 3.5-fold higher in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Lesion necrosis was also increased (6 fold) in apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Compared with apoE(-/-) mice, the spleens of apoE(-/-) MΦLRP1(-/-) mice contained 1.6- and 2.4-fold more total and Ly6-C(high) monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-C(high) and CC-chemokine receptor 2-positive cells in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice, suggesting that accumulation of apoptotic cells enhances lesion development and macrophage content by promoting the recruitment of inflammatory monocytes. CONCLUSION:Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE involving macrophage apoptosis and monocyte recruitment.
Authors: Cord Sunderkötter; Tatjana Nikolic; Marilyn J Dillon; Nico Van Rooijen; Martin Stehling; Douglas A Drevets; Pieter J M Leenen Journal: J Immunol Date: 2004-04-01 Impact factor: 5.422
Authors: Filip K Swirski; Mikael J Pittet; Moritz F Kircher; Elena Aikawa; Farouc A Jaffer; Peter Libby; Ralph Weissleder Journal: Proc Natl Acad Sci U S A Date: 2006-06-26 Impact factor: 11.205
Authors: Yankun Li; Robert F Schwabe; Tracie DeVries-Seimon; Pin Mei Yao; Marie-Christine Gerbod-Giannone; Alan R Tall; Roger J Davis; Richard Flavell; David A Brenner; Ira Tabas Journal: J Biol Chem Date: 2005-04-11 Impact factor: 5.157
Authors: Feng-Qiao Li; Gregory D Sempowski; Suzanne E McKenna; Daniel T Laskowitz; Carol A Colton; Michael P Vitek Journal: J Pharmacol Exp Ther Date: 2006-06-01 Impact factor: 4.030
Authors: A S Plump; J D Smith; T Hayek; K Aalto-Setälä; A Walsh; J G Verstuyft; E M Rubin; J L Breslow Journal: Cell Date: 1992-10-16 Impact factor: 41.582
Authors: Paul A Mueller; Lin Zhu; Hagai Tavori; Katherine Huynh; Ilaria Giunzioni; John M Stafford; MacRae F Linton; Sergio Fazio Journal: Circulation Date: 2018-10-23 Impact factor: 29.690
Authors: Hagai Tavori; Yan Ru Su; Patricia G Yancey; Ilaria Giunzioni; Ashley J Wilhelm; John L Blakemore; Manal Zabalawi; MacRae F Linton; Mary G Sorci-Thomas; Sergio Fazio Journal: J Lipid Res Date: 2015-01-15 Impact factor: 5.922
Authors: Amanda L Brown; Xuewei Zhu; Shunxing Rong; Swapnil Shewale; Jeongmin Seo; Elena Boudyguina; Abraham K Gebre; Martha A Alexander-Miller; John S Parks Journal: Arterioscler Thromb Vasc Biol Date: 2012-07-19 Impact factor: 8.311