title: Carbon Monoxide Potentiation of L-Type Ca2+Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis.
abstract: The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway induced in astrocytes after ischemic brain injury promotes vascular endothelial growth factor (VEGF) expression to maintain and repair neurovascular function. Although HO-1-derived CO has been shown to induce hypoxia-inducible factor-1α (HIF-1α)-dependent VEGF expression, the underlying mechanism independent of HIF-1α remains to be elucidated.
  
  
  
  HO-1 and VEGF were coexpressed in astrocytes of ischemic mouse brain tissues. Experiments with specific siRNAs and pharmacological activators/inhibitors of various target genes demonstrated that astrocytes pre-exposed to the CO-releasing compound, CORM-2, or transfected with HO-1 increased HIF-1α-independent VEGF expression via sequential activation of the following signal cascades; Ca2+/calmodulin-dependent protein kinase kinase β-mediated AMP-activated protein kinase (AMPK)α activation, AMPKα-induced increases in nicotinamide phosphoribosyltransferase (NAMPT) expression and cellular NAD+level, sirtuin 1 (SIRT1)-dependent peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) stabilization and activation, and PGC-1α/estrogen-related receptor (ERR)α-mediated VEGF expression. All of these sequential events were blocked by an L-type voltage-gated Ca2+channel inhibitor and Ca2+chelators, but not by other Ca2+channel inhibitors.
  
  
  
  HO-1-derived CO elicits Ca2+influx by activating L-type Ca2+channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway.
  
  
  
  Our results provide new mechanistic insight into the possible role for L-type Ca2+channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.|2 Department of Bioscience and Biotechnology, Konkuk University , Seoul, Republic of Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Kwang-Soon
authors.initials: KS
authors.lastname: Lee
authors.affiliation: 3 Department of Neurobiology, School of Medicine, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: 4 Department of Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
authors.affiliation: 5 Department of Life Sciences, College of Natural Sciences, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: 6 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University , Seoul, Republic of Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D020746:Calcium Channels, L-Type; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D056564:Sirtuin 1; D042461:Vascular Endothelial Growth Factor A; D000097983:ERRalpha Estrogen-Related Receptor; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C496541:HMOX1 protein, human; C447939:SIRT1 protein, human
keywords: L-type voltage-gated Ca2+ channel; astrocytes; carbon monoxide; heme oxygenase-1; ischemic stroke; vascular endothelial growth factor