| First Author | Choi YK | Year | 2018 |
| Journal | PLoS One | Volume | 13 |
| Issue | 8 | Pages | e0202039 |
| PubMed ID | 30153269 | Mgi Jnum | J:265342 |
| Mgi Id | MGI:6199235 | Doi | 10.1371/journal.pone.0202039 |
| Citation | Choi YK, et al. (2018) Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1alpha/ERRalpha circuit. PLoS One 13(8):e0202039 |
| abstractText | Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the hypoxia-inducible factor-1alpha (HIF-1alpha) and peroxisome-proliferator-activating receptor-gamma coactivator-1alpha (PGC-1alpha)/estrogen-related receptor alpha (ERRalpha) pathways, respectively, in astrocytes. However, evidence of cross-talk between both pathways in HO metabolite-mediated mitochondrial biogenesis has not been well elucidated. Here, we found that HIF-1alpha was upregulated in astrocytes after ischemic brain injury following exposure to the carbon monoxide (CO)-releasing compound CORM-2. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HIF-1alpha levels were highly correlated with increased PGC-1alpha and ERRalpha levels, which were linked to the HO metabolites CO- and bilirubin-induced activation of apical L-type Ca2+ channel and sequential Ca2+-dependent signal transduction. Moreover, HIF-1alpha was stabilized in a proline hydroxylase-dependent manner by transient induction of intracellular hypoxia via the PGC-1alpha/ERRalpha-induced increases in mitochondrial biogenesis and oxygen consumption. HIF-1alpha knockdown blocked HO-1 system-mediated transcriptional expression of ERRalpha, but not of PGC-1alpha, suggesting a possible involvement of HIF-1alpha in ERRalpha-mediated mitochondrial biogenesis. These data suggest that the HO-1-derived metabolites, CO and bilirubin, elevate astrocytic mitochondrial function via a HIF-1alpha/ERRalpha circuit coupled with L-type Ca2+ channel activation and PGC-1alpha-mediated oxygen consumption. This circuit may play an important role in repairing neurovascular function after focal ischemic brain injury by stimulating mitochondrial biogenesis. |
