title: Regulation of high-density lipoprotein on hematopoietic stem/progenitor cells in atherosclerosis requires scavenger receptor type BI expression.
abstract: OBJECTIVE
  Recently, we demonstrated that scavenger receptor type BI (SR-BI), a high-density lipoprotein (HDL) receptor, was expressed on murine hematopoietic stem/progenitor cells (HSPC) and infusion of reconstituted HDL and purified human apolipoprotein A-I (apoA-I) suppressed HSPC proliferation. We hypothesized that SR-B1 expression is required for the observed antiproliferative effects of HDL on HSPC.
  
  
  RESULTS
  SR-BI-deficient (SR-BI(-/-)) mice and wild-type controls were fed on chow or high-fat diet (HFD) for 8 to 10 weeks. Under chow diet, a significant increase in Lin(-) Sca1(+) cKit(+) cells (LSK cells, so-called HSPC) was found in the bone marrow of SR-BI(-/-) mice when compared with wild-type mice. HFD induced a further expansion of CD150(+)CD48(-) LSK cells (HSC), HSPC, and granulocyte monocyte progenitors in SR-BI(-/-) mice. Injection of reactive oxygen species inhibitor N-acetylcysteine attenuated HFD-induced HSPC expansion, leukocytosis, and atherosclerosis in SR-BI(-/-) mice. ApoA-I infusion inhibited HSPC cell proliferation, Akt phosphorylation and reactive oxygen species production in HSPC and plaque progression in low-density lipoprotein receptor knockout (LDLr(-/-)) apoA-I(-/-) mice on HFD but had no effect on SR-BI(-/-) mice on HFD. Transplantation of SR-BI(-/-) bone marrow cells into irradiated LDLr(-/-) recipients resulted in enhanced white blood cells reconstitution, inflammatory cell production, and plaque development. In patients with coronary heart disease, HDL levels were negatively correlated with white blood cells count and HSPC frequency in the peripheral blood. By flow cytometry, SR-BI expression was detected on human HSPC.
  
  
  CONCLUSIONS
  SR-BI plays a critical role in the HDL-mediated regulation HSPC proliferation and differentiation, which is associated with atherosclerosis progression.
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Mingming
authors: M
authors: Gao
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Dong
authors: D
authors: Zhao
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Sarah
authors: S
authors: Schouteden
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Mary G
authors: MG
authors: Sorci-Thomas
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Paul P
authors: PP
authors: Van Veldhoven
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Kristel
authors: K
authors: Eggermont
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: George
authors: G
authors: Liu
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.).
authors: Catherine M
authors: CM
authors: Verfaillie
authors: From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (M.G., G.L.); Beijing Key Laboratory of Diabetes Research and Care, LuHe Hospital, Capital University, Peking, China (D.Z.); Interdepartmental Stem Cell Institute (S.S., K.E., C.M.V., Y.F.) and Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine (P.P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; and Section on Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (M.G.S.-T.). yingmei.feng@med.kuleuven.be catherine.verfaillie@med.kuleuven.be.
authors: Yingmei
authors: Y
authors: Feng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects; D004036:Diet, Atherogenic / Q000009:adverse effects; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics; D007964:Leukocytosis / Q000209:etiology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011828:Radiation Chimera; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000097:blood* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000111:Acetylcysteine
keywords: HDL; atherosclerosis; cholesterol