Heme oxygenase-1 modulates microRNA expression in cultured astroglia: Implications for chronic brain disorders

• Published in: Glia Vol. 63; no. 7; pp. 1270 - 1284
• Main Authors: Lin, Shih-Hsiung, Song, Wei, Cressatti, Marisa, Zukor, Hillel, Wang, Eugenia, Schipper, Hyman M.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.07.2015; Wiley Subscription Services, Inc
• Subjects: Animals; astrocyte; Astrocytes - metabolism; Bilirubin - metabolism; Brain - metabolism; Brain Diseases - metabolism; Carbon Monoxide - metabolism; heme oxygenase-1; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Iron - metabolism; MicroRNAs - metabolism; miRNA; mitochondria; neurodegeneration; oxidative stress; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Transfection; neurodegeneration; miRNA; heme oxygenase-1; astrocyte; mitochondria; oxidative stress
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22823

Background Over‐expression of the heme‐degrading enzyme, heme oxygenase‐1 (HO‐1) promotes iron deposition, mitochondrial damage, and autophagy in astrocytes and enhances the vulnerability of nearby neuronal constituents to oxidative injury. These neuropathological features and aberrant brain microRNA (miRNA) expression patterns have been implicated in the etiopathogeneses of various neurodevelopmental and aging‐related neurodegenerative disorders. Objective To correlate glial HO‐1 overexpression with altered miRNA patterns, which have been linked to the aforementioned “core” neuropathological features. Methods miRNA microchip assays were performed on HMOX1‐ and sham‐transfected primary rat astroglia and affected miRNAs were further validated by qPCR. The roles of the heme degradation products, carbon monoxide (CO), iron (Fe) and bilirubin on miRNA expression were assessed and salient mRNA targets of the impacted miRNAs were ascertained. Results In HMOX1‐transfected astrocytes, rno‐miR‐140*, rno‐miR‐17, and rno‐miR‐16 were significantly up‐regulated, and rno‐miR‐297, rno‐miR‐206, rno‐miR‐187, rno‐miR‐181a, rno‐miR‐138 and rno‐miR‐29c were down‐regulated, compared to sham‐transfected controls. CO and Fe were implicated in the HMOX1 effects, whereas bilirubin was inert or counteracted the HMOX1‐related changes. mRNA levels of Ngfr, Vglut1, Mapk3, Tnf‐α, and Sirt1, known targets of the down‐regulated miRNAs and abnormal in various human brain disorders, were significantly increased in the HMOX‐1‐transfected astrocytes. Conclusions In chronic CNS disorders, altered expression of salient miRNAs and their mRNA targets may contribute to the neural damage accruing from the over‐expression of glial HO‐1. © 2015 Wiley Periodicals, Inc. GLIA 2015;63:1270–1284 Main Points HMOX1‐transfection in astrocytes dys‐regulates rno‐miR‐140*, ‐17, ‐16 ‐297, ‐ 206, ‐187, ‐181a, ‐138 and ‐29c. Carbon monoxide and iron mediate the HMOX1 effects, whereas bilirubin is inert or counteracts the HMOX1‐related changes. The dys‐regulated miRNAs may contribute to mitochondrial damage and mitophagy in HMOX1‐transfected glia.