Research Papers:

LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118

Gang Yao _, Qi Zhang, Thorsten R. Doeppner, Feng Niu, Qiaochuan Li, Yanping Yang, Ulrike Kuckelkorn, Nina Hagemann, Wei Li, D.M. Hemann, Wen Zhou and Fengyan Jin

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Oncotarget. 2015; 6:30251-30262. https://doi.org/10.18632/oncotarget.4943

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Gang Yao1,2,*, Qi Zhang1,*, Thorsten R. Doeppner3, Feng Niu1, Qiaochuan Li4, Yanping Yang1, Ulrike Kuckelkorn5, Nina Hagemann3, Wei Li1, Dirk M. Hermann3, Yun Dai6, Wen Zhou7, Fengyan Jin1

1Cancer Center, the First Affiliated Hospital, Jilin University, Changchun, Jilin, China

2Department of Neurology, the Second Affiliated Hospital, Jilin University, Changchun, Jilin, China

3Department of Neurology, University Hospital Essen, Essen, Germany

4Department of Hematology, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China

5Department of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany

6Department of Medicine, Virginia Commonwealth University, Massey Cancer Center, Richmond, Virginia, USA

7Cancer 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

*These authors have contributed equally to this work

Correspondence to:

Fengyan Jin, e-mail: [email protected]

Wen Zhou, e-mail: [email protected]

Keywords: low-density lipoprotein, HIF, NF-κB, proteasome inhibitor, angiogenesis

Received: March 06, 2015     Accepted: September 04, 2015     Published: September 15, 2015


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.

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