title: Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway.
abstract: OBJECTIVE
  The role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation.
  
  
  RESULTS
  Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase-1(-/-)/ApoE(-/-) mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE(-/-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway.
  
  
  CONCLUSIONS
  Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Yin
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Sha
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Jietang
authors.initials: J
authors.lastname: Mai
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Anthony
authors.initials: A
authors.lastname: Virtue
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Jahaira
authors.initials: J
authors.lastname: Lopez-Pastrana
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: M Alexandra
authors.initials: MA
authors.lastname: Monroy
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.).
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research (Y.Y., X.L., X.S., H.X., Y.-F.L., Y.S., J.M., A.V., J.L.-P., S.M., M.A.M., E.T.C., X.J., H.W., X.-F.Y.), Center for Translational Medicine (D.G.T.), Department of Pharmacology (Y.Y., X.L., X.S., H.X., Y.-F.L, Y.S., J.M., A.V., J.L.-P., S.M., D.G.T., X.J., H.W., X.-F.Y.), and Department of Surgery (M.A.M., E.T.C.), Temple University School of Medicine, Philadelphia, PA; and NIH Chemical Genomics Center, Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (C.J.T.). xfyang@temple.edu.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D006949:Hyperlipidemias / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D061945:Caspase Inhibitors; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D020170:Caspase 1; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: atherosclerosis; caspase-1; inflammation