title: Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis: A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA.
abstract: Deficient angiogenesis may contribute to worsen the prognosis of myocardial ischemia, peripheral arterial disease, ischemic stroke, etc. Dyslipidemic and inflammatory environments attenuate endothelial cell (EC) proliferation and angiogenesis, worsening the prognosis of ischemia. Under these dyslipidemic and inflammatory environments, EC-caspase-1 becomes activated and induces inflammatory cell death that is defined as pyroptosis. However, the underlying mechanism that correlates caspase-1 activation with angiogenic impairment and the prognosis of ischemia remains poorly defined. By using flow cytometric analysis, enzyme and receptor inhibitors, and hind limb ischemia model in caspase-1 knock-out (KO) mice, we examined our novel hypothesis, i.e. inhibition of caspase-1 in ECs under dyslipidemic and inflammatory environments attenuates EC pyroptosis, improves EC survival mediated by vascular endothelial growth factor receptor 2 (VEGFR-2), angiogenesis, and the prognosis of ischemia. We have made the following findings. Proatherogenic lipids induce higher caspase-1 activation in larger sizes of human aortic endothelial cells (HAECs) than in smaller sizes of HAECs. Proatherogenic lipids increase pyroptosis significantly more in smaller sizes of HAECs than in larger sizes of the cells. VEGFR-2 inhibition increases caspase-1 activation in HAECs induced by lysophosphatidylcholine treatment. Caspase-1 activation inhibits VEGFR-2 expression. Caspase-1 inhibition improves the tube formation of lysophosphatidylcholine-treated HAECs. Finally, caspase-1 depletion improves angiogenesis and blood flow in mouse hind limb ischemic tissues. Our results have demonstrated for the first time that inhibition of proatherogenic caspase-1 activation in ECs improves angiogenesis and the prognosis of ischemia.
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research.
authors.forename: Jahaira
authors.initials: J
authors.lastname: Lopez-Pastrana
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, the Department of Bioengineering, University of Illinois-Urbana Champaign, Urbana, Illinois 61801.
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Ferrer
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research.
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Xiong
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Ramon
authors.initials: R
authors.lastname: Cueto
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research.
authors.forename: Jun
authors.initials: J
authors.lastname: Nelson
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Sha
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Cannella
authors.affiliation: the Department of Bioengineering, University of Illinois-Urbana Champaign, Urbana, Illinois 61801.
authors.forename: Princess I
authors.initials: PI
authors.lastname: Imoukhuede
authors.affiliation: Neuroscience, and.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qin
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Departments of Pharmacology, xfyang@temple.edu.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D008055:Lipids; C000588866:KDR protein, human; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D020170:Caspase 1
keywords: angiogenesis; caspase 1 (CASP1); inflammation; ischemia; vascular endothelial growth factor (VEGF)