title: Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.
abstract: Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-(1+)) stem/progenitor cells and weakening their angiogenic ability. Using biochemical methods, gene knockout, cell therapy and myocardial infarction (MI) models, we had the following findings: 1) Hyperlipidemia induces caspase-1 activity in mouse Sca-(1+) progenitor cells in vivo; 2) Caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell death-related gene expression in vivo; 3) Injection of Sca-1+ progenitor cells from caspase-1(-/-) mice improves endothelial capillary density in heart and decreases cardiomyocyte death in a mouse model of MI; and 4) Caspase-1(-/-) Sca-(1+) progenitor cell therapy improves mouse cardiac function after MI. Our results provide insight on how hyperlipidemia activates caspase-1 in Sca-(1+) progenitor cells, which subsequently weakens Sca-(1+) progenitor cell repair of vasculature injury. These results demonstrate the therapeutic potential of caspase-1 inhibition in improving progenitor cell therapy for MI.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China.
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital to Nanchang University, Nanchang, JiangXi 330006, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital to Nanchang University, Nanchang, JiangXi 330006, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Gong
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center.
authors.forename: Jun
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Center for Translational Medicine, Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Cardiovascular Research Center.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Center for Translational Medicine, Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Center for Translational Medicine, Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China, huangcongxin1951@163.com.
authors.forename: Cong-Xin
authors.initials: CX
authors.lastname: Huang
authors.affiliation: Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences(307 Hospital, PLA), No.8 DongDa Road, FengTai Area, Beijing, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Cardiovascular Research Center.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D006949:Hyperlipidemias / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000166:cytology*
chemical_list: D020170:Caspase 1