Carbon Monoxide Potentiation of L-Type Ca 2+ Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis

Yoon Kyung Choi, Ji Hee Kim, Dong Keun Lee, Kwang Soon Lee, Moo Ho Won, Dooil Jeoung, Hansoo Lee, Kwon Soo Ha, Young-Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aims: 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. Results: 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; Ca 2+ /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 Ca 2+ channel inhibitor and Ca 2+ chelators, but not by other Ca 2+ channel inhibitors. Innovation: HO-1-derived CO elicits Ca 2+ influx by activating L-type Ca 2+ channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway. Conclusion: Our results provide new mechanistic insight into the possible role for L-type Ca 2+ channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.

Original languageEnglish
Pages (from-to)20-36
Number of pages17
JournalAntioxidants and Redox Signaling
Volume27
Issue number1
DOIs
Publication statusPublished - 2017 Jul 1

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Sirtuin 1
Hypoxia-Inducible Factor 1
AMP-Activated Protein Kinases
Heme Oxygenase-1
Carbon Monoxide
Vascular Endothelial Growth Factor A
Nicotinamide Phosphoribosyltransferase
Astrocytes
Chemical activation
Brain
Calcium-Calmodulin-Dependent Protein Kinases
Peroxisome Proliferator-Activated Receptors
Vascular Endothelial Growth Factor Receptor
Chelating Agents
NAD
Brain Injuries
Oxidation-Reduction
ERRalpha estrogen-related receptor
Estrogens
Repair

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Choi, Yoon Kyung ; Kim, Ji Hee ; Lee, Dong Keun ; Lee, Kwang Soon ; Won, Moo Ho ; Jeoung, Dooil ; Lee, Hansoo ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / Carbon Monoxide Potentiation of L-Type Ca 2+ Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis In: Antioxidants and Redox Signaling. 2017 ; Vol. 27, No. 1. pp. 20-36.
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abstract = "Aims: 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. Results: 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; Ca 2+ /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 Ca 2+ channel inhibitor and Ca 2+ chelators, but not by other Ca 2+ channel inhibitors. Innovation: HO-1-derived CO elicits Ca 2+ influx by activating L-type Ca 2+ channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway. Conclusion: Our results provide new mechanistic insight into the possible role for L-type Ca 2+ channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.",
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Carbon Monoxide Potentiation of L-Type Ca 2+ Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis . / Choi, Yoon Kyung; Kim, Ji Hee; Lee, Dong Keun; Lee, Kwang Soon; Won, Moo Ho; Jeoung, Dooil; Lee, Hansoo; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Antioxidants and Redox Signaling, Vol. 27, No. 1, 01.07.2017, p. 20-36.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Carbon Monoxide Potentiation of L-Type Ca 2+ Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis

AU - Choi, Yoon Kyung

AU - Kim, Ji Hee

AU - Lee, Dong Keun

AU - Lee, Kwang Soon

AU - Won, Moo Ho

AU - Jeoung, Dooil

AU - Lee, Hansoo

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Aims: 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. Results: 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; Ca 2+ /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 Ca 2+ channel inhibitor and Ca 2+ chelators, but not by other Ca 2+ channel inhibitors. Innovation: HO-1-derived CO elicits Ca 2+ influx by activating L-type Ca 2+ channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway. Conclusion: Our results provide new mechanistic insight into the possible role for L-type Ca 2+ channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.

AB - Aims: 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. Results: 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; Ca 2+ /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 Ca 2+ channel inhibitor and Ca 2+ chelators, but not by other Ca 2+ channel inhibitors. Innovation: HO-1-derived CO elicits Ca 2+ influx by activating L-type Ca 2+ channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway. Conclusion: Our results provide new mechanistic insight into the possible role for L-type Ca 2+ channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.

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