Carbon Monoxide Potentiation of L-Type Ca2+ 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 journalArticlepeer-review

26 Citations (Scopus)


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; 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. Innovation: 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. Conclusion: 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.

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

Bibliographical note

Publisher Copyright:
© Copyright 2017, Mary Ann Liebert, Inc. 2017.

All Science Journal Classification (ASJC) codes

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


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