Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C high monocytosis

Evidence that the effects are not apolipoprotein e dependent

Patricia G. Yancey, Yu Ding, Daping Fan, John L. Blakemore, Youmin Zhang, Lei Ding, Jiabao Zhang, MacRae F. Linton, Sergio Fazio

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Bacground-: 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 Result-: 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 monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-Chigh 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.

Original languageEnglish (US)
Pages (from-to)454-464
Number of pages11
JournalCirculation
Volume124
Issue number4
DOIs
StatePublished - Jul 26 2011
Externally publishedYes

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Low Density Lipoprotein Receptor-Related Protein-1
Apolipoproteins
Apolipoproteins E
Atherosclerosis
Macrophages
LDL Receptors
Pyroptosis
Monocytes
Proteins
CCR2 Receptors
Apoptosis

Keywords

  • apolipoproteins E
  • apoptosis
  • atherosclerosis
  • low-density lipoprotein receptor-related protein 1
  • Ly6-C antigen, mouse
  • monocytes

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C high monocytosis : Evidence that the effects are not apolipoprotein e dependent. / Yancey, Patricia G.; Ding, Yu; Fan, Daping; Blakemore, John L.; Zhang, Youmin; Ding, Lei; Zhang, Jiabao; Linton, MacRae F.; Fazio, Sergio.

In: Circulation, Vol. 124, No. 4, 26.07.2011, p. 454-464.

Research output: Contribution to journalArticle

Yancey, Patricia G. ; Ding, Yu ; Fan, Daping ; Blakemore, John L. ; Zhang, Youmin ; Ding, Lei ; Zhang, Jiabao ; Linton, MacRae F. ; Fazio, Sergio. / Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C high monocytosis : Evidence that the effects are not apolipoprotein e dependent. In: Circulation. 2011 ; Vol. 124, No. 4. pp. 454-464.
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abstract = "Bacground-: 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 Result-: 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 monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-Chigh 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.",
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AU - Ding, Yu

AU - Fan, Daping

AU - Blakemore, John L.

AU - Zhang, Youmin

AU - Ding, Lei

AU - Zhang, Jiabao

AU - Linton, MacRae F.

AU - Fazio, Sergio

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N2 - Bacground-: 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 Result-: 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 monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-Chigh 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.

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