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. 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.
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.
Authors: Daqing Zhang; Xiaohua Jiang; Pu Fang; Yan Yan; Jian Song; Sapna Gupta; Andrew I Schafer; William Durante; Warren D Kruger; Xiaofeng Yang; Hong Wang Journal: Circulation Date: 2009-10-26 Impact factor: 29.690
Authors: Edward A Miao; Irina A Leaf; Piper M Treuting; Dat P Mao; Monica Dors; Anasuya Sarkar; Sarah E Warren; Mark D Wewers; Alan Aderem Journal: Nat Immunol Date: 2010-11-07 Impact factor: 25.606
Authors: Xinyuan Li; Pu Fang; William Y Yang; Kylie Chan; Muriel Lavallee; Keman Xu; Tracy Gao; Hong Wang; Xiaofeng Yang Journal: Can J Physiol Pharmacol Date: 2016-11-05 Impact factor: 2.273
Authors: Jahaira Lopez-Pastrana; Lucas M Ferrer; Ya-Feng Li; Xinyu Xiong; Hang Xi; Ramon Cueto; Jun Nelson; Xiaojin Sha; Xinyuan Li; Ann L Cannella; Princess I Imoukhuede; Xuebin Qin; Eric T Choi; Hong Wang; Xiao-Feng Yang Journal: J Biol Chem Date: 2015-06-02 Impact factor: 5.157
Authors: Lucas M Ferrer; Alexandra M Monroy; Jahaira Lopez-Pastrana; Gayani Nanayakkara; Ramon Cueto; Ya-Feng Li; Xinyuan Li; Hong Wang; Xiao-Feng Yang; Eric T Choi Journal: J Cardiovasc Transl Res Date: 2016-02-29 Impact factor: 4.132
Authors: Xinyuan Li; Ying Shao; Xiaojin Sha; Pu Fang; Yin-Ming Kuo; Andrew J Andrews; Yafeng Li; William Y Yang; Massimo Maddaloni; David W Pascual; Jin J Luo; Xiaohua Jiang; Hong Wang; Xiaofeng Yang Journal: Arterioscler Thromb Vasc Biol Date: 2018-01-25 Impact factor: 8.311
Authors: Ying Shao; Valeria Chernaya; Candice Johnson; William Y Yang; Ramon Cueto; Xiaojin Sha; Yi Zhang; Xuebin Qin; Jianxin Sun; Eric T Choi; Hong Wang; Xiao-feng Yang Journal: J Cardiovasc Transl Res Date: 2016-01-08 Impact factor: 4.132