Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway

Ying Yin; Xinyuan Li; Xiaojin Sha; Hang Xi; Ya-Feng Li; Ying Shao; Jietang Mai; Anthony Virtue; Jahaira Lopez-Pastrana; Shu Meng; Douglas G Tilley; M Alexandra Monroy; Eric T Choi; Craig J Thomas; Xiaohua Jiang; Hong Wang; Xiao-Feng Yang

doi:10.1161/ATVBAHA.115.305282

Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway

Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):804-16. doi: 10.1161/ATVBAHA.115.305282. Epub 2015 Feb 19.

Authors

Ying Yin¹, Xinyuan Li¹, Xiaojin Sha¹, Hang Xi¹, Ya-Feng Li¹, Ying Shao¹, Jietang Mai¹, Anthony Virtue¹, Jahaira Lopez-Pastrana¹, Shu Meng¹, Douglas G Tilley¹, M Alexandra Monroy¹, Eric T Choi¹, Craig J Thomas¹, Xiaohua Jiang¹, Hong Wang¹, Xiao-Feng Yang²

Affiliations

¹ 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.).
² 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.

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.

Approach and 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.

Keywords: atherosclerosis; caspase-1; inflammation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Aortic Diseases / enzymology*
Aortic Diseases / genetics
Aortic Diseases / immunology
Aortic Diseases / pathology
Aortic Diseases / prevention & control
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Atherosclerosis / enzymology*
Atherosclerosis / genetics
Atherosclerosis / immunology
Atherosclerosis / pathology
Atherosclerosis / prevention & control
Bone Marrow Transplantation
Caspase 1 / deficiency
Caspase 1 / genetics
Caspase 1 / metabolism*
Caspase Inhibitors / pharmacology
Cell Adhesion Molecules / metabolism
Cells, Cultured
Cytokines / metabolism
Disease Models, Animal
Endothelial Cells / drug effects
Endothelial Cells / enzymology*
Endothelial Cells / immunology
Enzyme Activation
Gene Expression Regulation
Humans
Hyperlipidemias / enzymology*
Hyperlipidemias / genetics
Hyperlipidemias / immunology
Inflammation Mediators / metabolism
Lipoproteins, LDL / metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Monocytes / enzymology
Monocytes / immunology
Reactive Oxygen Species / metabolism
Signal Transduction
Sirtuin 1 / metabolism*
Time Factors
Transcription Factor AP-1 / metabolism

Substances

Apolipoproteins E
Caspase Inhibitors
Cell Adhesion Molecules
Cytokines
Inflammation Mediators
Lipoproteins, LDL
Reactive Oxygen Species
Transcription Factor AP-1
oxidized low density lipoprotein
Caspase 1
SIRT1 protein, human
Sirt1 protein, mouse
Sirtuin 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding