PMID- 21597006 OWN - NLM STAT- MEDLINE DCOM- 20110920 LR - 20211020 IS - 1524-4636 (Electronic) IS - 1079-5642 (Print) IS - 1079-5642 (Linking) VI - 31 IP - 8 DP - 2011 Aug TI - Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase alpha subunits. PG - 1757-65 LID - 10.1161/ATVBAHA.111.227991 [doi] AB - OBJECTIVE: The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo. METHODS AND RESULTS: Angiogenesis was assayed by monitoring endothelial tube formation (a surrogate for angiogenesis) in human umbilical vein endothelial cells (ECs), isolated mouse aortic endothelial cells (MAECs), and pulmonary microvascular endothelial cells or in ischemic thigh adductor muscles from wild-type (WT) mice or mice deficient in either AMPKalpha1 or AMPKalpha2. AMPK inhibition with pharmacological inhibitor (compound C) or genetic means (transfection of AMPKalpha-specific small interfering RNA) significantly lowered the tube formation in human umbilical vein ECs. Consistently, compared with WT mice, tube formation in MAECs isolated from either AMPKalpha1(-/-) or AMPKalpha2(-/-) mice, which exhibited oxidative stress and reduced expression of UCP2, was significantly impaired. In addition, adenoviral overexpression of UCP2, but not adenoviruses encoding green fluorescent protein, normalized tube formation in MAECs from either AMPKalpha1(-/-) or AMPKalpha2(-/-) mice. Similarly, supplementation with sodium nitroprusside, a nitric oxide (NO) donor, restored tube formation. Furthermore, ischemia significantly increased angiogenesis, serine 1177 phosphorylation of endothelial NO synthase, and UCP2 in ischemic thigh adductor muscles from WT mice but not in those from either AMPKalpha1(-/-) or AMPKalpha2(-/-) mice. CONCLUSIONS: We conclude that AMPK-dependent UCP2 expression in ECs promotes angiogenesis in vivo. FAU - Xu, Ming-Jiang AU - Xu MJ AD - Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA. FAU - Song, Ping AU - Song P FAU - Shirwany, Najeeb AU - Shirwany N FAU - Liang, Bin AU - Liang B FAU - Xing, Junjie AU - Xing J FAU - Viollet, Benoit AU - Viollet B FAU - Wang, Xian AU - Wang X FAU - Zhu, Yi AU - Zhu Y FAU - Zou, Ming-Hui AU - Zou MH LA - eng GR - HL074399/HL/NHLBI NIH HHS/United States GR - R01 HL080499-04/HL/NHLBI NIH HHS/United States GR - HL080499/HL/NHLBI NIH HHS/United States GR - R01 HL079584-07/HL/NHLBI NIH HHS/United States GR - R01 HL079584-09/HL/NHLBI NIH HHS/United States GR - R01 HL074399-07/HL/NHLBI NIH HHS/United States GR - HL110448/HL/NHLBI NIH HHS/United States GR - R01 HL079584/HL/NHLBI NIH HHS/United States GR - R01 HL074399-08/HL/NHLBI NIH HHS/United States GR - R44 HL110448/HL/NHLBI NIH HHS/United States GR - R01 HL074399-06/HL/NHLBI NIH HHS/United States GR - R01 HL110488-01/HL/NHLBI NIH HHS/United States GR - HL096032/HL/NHLBI NIH HHS/United States GR - R01 HL105157-02/HL/NHLBI NIH HHS/United States GR - R01 HL089920/HL/NHLBI NIH HHS/United States GR - R01 HL074399/HL/NHLBI NIH HHS/United States GR - HL089920/HL/NHLBI NIH HHS/United States GR - HL079584/HL/NHLBI NIH HHS/United States GR - HL105157/HL/NHLBI NIH HHS/United States GR - R01 HL110488/HL/NHLBI NIH HHS/United States GR - R01 HL080499-05/HL/NHLBI NIH HHS/United States GR - R01 HL105157/HL/NHLBI NIH HHS/United States GR - R01 HL105157-03/HL/NHLBI NIH HHS/United States GR - R01 HL079584-08/HL/NHLBI NIH HHS/United States GR - R01 HL096032-03/HL/NHLBI NIH HHS/United States GR - R43 HL110448/HL/NHLBI NIH HHS/United States GR - R01 HL096032-04/HL/NHLBI NIH HHS/United States GR - R01 HL080499/HL/NHLBI NIH HHS/United States GR - R01 HL089920-03/HL/NHLBI NIH HHS/United States GR - R01 HL110488-02/HL/NHLBI NIH HHS/United States GR - R01 HL096032/HL/NHLBI NIH HHS/United States GR - R01 HL089920-04/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110519 PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (Ion Channels) RN - 0 (Membrane Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (Nitric Oxide Donors) RN - 0 (Phosphoproteins) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Nitrogen Species) RN - 0 (UCP2 protein, human) RN - 0 (Ucp2 protein, mouse) RN - 0 (Ucp2 protein, rat) RN - 0 (Uncoupling Protein 2) RN - 0 (p112 protein, rat) RN - 169D1260KM (Nitroprusside) RN - EC 1.14.13.39 (NOS3 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 2.7.11.1 (AMPK alpha1 subunit, mouse) RN - EC 2.7.11.1 (AMPK alpha2 subunit, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*deficiency/genetics/metabolism MH - Animals MH - Cells, Cultured MH - Endothelial Cells/drug effects/metabolism/pathology MH - Gene Expression MH - Gene Silencing MH - Humans MH - Ion Channels/genetics/*metabolism MH - Ischemia/genetics/*metabolism/pathology MH - Male MH - Membrane Proteins MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mitochondrial Proteins/genetics/*metabolism MH - Neovascularization, Physiologic MH - Nitric Oxide Donors/pharmacology MH - Nitric Oxide Synthase Type III/metabolism MH - Nitroprusside/pharmacology MH - Phosphoproteins MH - Phosphorylation MH - RNA, Small Interfering/genetics MH - Reactive Nitrogen Species/metabolism MH - Signal Transduction MH - Uncoupling Protein 2 PMC - PMC3158995 MID - NIHMS303041 EDAT- 2011/05/21 06:00 MHDA- 2011/09/21 06:00 PMCR- 2012/08/01 CRDT- 2011/05/21 06:00 PHST- 2011/05/21 06:00 [entrez] PHST- 2011/05/21 06:00 [pubmed] PHST- 2011/09/21 06:00 [medline] PHST- 2012/08/01 00:00 [pmc-release] AID - ATVBAHA.111.227991 [pii] AID - 10.1161/ATVBAHA.111.227991 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2011 Aug;31(8):1757-65. doi: 10.1161/ATVBAHA.111.227991. Epub 2011 May 19.