title: LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118.
abstract: Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure. Significantly, the proteasome inhibitor BSc2118 prevented angiogenesis attenuation by LDL through restoring expression of HIFs. Together, these findings argue that HIF-1β might act as a novel cross-link between the HIF and NF-κB pathways in suppression of angiogenesis by LDL, while proteasome inhibitors might promote angiogenesis by reactivating this signaling cascade under hyperlipidemia.
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.|Department of Neurology, The Second Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University Hospital Essen, Essen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Niu
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Qiaochuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.affiliation: Department of Neurology, University Hospital Essen, Essen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hagemann
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurology, University Hospital Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Massey Cancer Center, Richmond, Virginia, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Changsha, Hunan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Jin
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000098:blood supply*; D002073:Butanes / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002073:Butanes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D009842:Oligopeptides; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C513723:BSc2118; C497442:HIF1A protein, human
keywords: HIF; NF-κB; angiogenesis; low-density lipoprotein; proteasome inhibitor