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miRNA-27a-3p and miRNA-222-3p as Novel Modulators of Phosphodiesterase 3a (PDE3A) in Cerebral Microvascular Endothelial Cells

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Abstract

Endothelial dysfunction is a key element in cerebral small vessel disease (CSVD), which may cause stroke and cognitive decline. Cyclic nucleotide signaling modulates endothelial function. The cyclic adenosine monophosphate-degrading enzyme phosphodiesterase 3 (PDE3) is an important treatment target which may be modulated by microRNAs (miRNAs) important for regulating gene expression. We aimed to identify PDE3-targeting miRNAs to highlight potential therapeutic targets for endothelial dysfunction and CSVD. PDE3-targeting miRNAs were identified by in silico analysis (TargetScan, miRWalk, miRanda, and RNA22). The identified miRNAs were ranked on the basis of TargetScan context scores and their expression (log2 read counts) in a human brain endothelial cell line (hCMEC/D3) described recently. miRNAs were subjected to co-expression meta-analysis (CoMeTa) to create miRNA clusters. The pathways targeted by the miRNAs were assigned functional annotations via the KEGG pathway and COOL. hCMEC/D3 cells were transfected with miRNA mimics miR-27a-3p and miR-222-3p, and the effect on PDE3A protein expression was analyzed by Western blotting. Only PDE3A is expressed in hCMEC/D3 cells. The in silico prediction identified 67 PDE3A-related miRNAs, of which 49 were expressed in hCMEC/D3 cells. Further analysis of the top two miRNA clusters (miR-221/miR-222 and miR-27a/miR-27b/miR-128) indicated a potential link to pathways relevant to cerebral and vascular integrity and repair. hCMEC/D3 cells transfected with miR-27a-3p and miR-222-3p mimics had reduced relative expression of PDE3A protein. PDE3A-related miRNAs miR-221/miR-222 and miR-27a/miR-27b/miR-128 are potentially linked to pathways essential for immune regulation as well as cerebral and vascular integrity/function. Furthermore, relative PDE3A protein expression was reduced by miR27a-3p and miR-222-3p.

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Funding

This work was funded by the Herlev Research Council. S.Y. is supported by the Department of Neurology, Herlev University Hospital. Running costs are supported by the Aase and Ejnar Danielsens Foundation, the Fonden for Lægevidenskabens Fremme, the Novo Nordic Foundation, and Direktør Jacob Madsen og Hustru Olga Madsens Fond.

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Authors and Affiliations

  1. Stroke Unit and Neurovascular Research Unit, Department of Neurology, Herlev and Gentofte Hospital, Herlev ringvej 75, Herlev, Denmark

    S. Yasmeen & C. Kruuse

  2. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    S. Yasmeen, A. H. Mirza, B. Brodin, F. Pociot & C. Kruuse

  3. Pediatric Department, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark

    S. Kaur, A. H. Mirza & F. Pociot

  4. Steno Diabetes Center Copenhagen, Niels Steensens vej 2-4, 2820, Gentofte, Denmark

    S. Kaur & F. Pociot

  5. CNS Drug Delivery and Barrier Modelling, University of Copenhagen, Nørre alle 67, Copenhagen, Denmark

    B. Brodin

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  1. S. Yasmeen
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  2. S. Kaur
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Contributions

Study concept and design: CK, AHM, SY, SK, and FP; acquisition of data: SK, AHM and SY; analysis and interpretation of data: SY, SK, CK, FP and BB; drafting of the manuscript: SY; critical revision of the manuscript for important intellectual content: SY, SK, CK, FP, AHM, and BB; approval of final manuscript: CK, SY, SK, FP, BB and AHM; obtained funding: SY and CK; study supervision, CK, FP and BB.

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Correspondence to C. Kruuse.

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Highlights

• Cyclic nucleotides are essential in endothelial cell function.

• The cAMP degrading phosphodiesterase 3 (PDE3) is a target in stroke treatment.

• PDE3A is expressed in cerebral microvascular endothelial cells.

• PDE3A-associated miRNAs likely regulate cerebral microvascular endothelial function.

• PDE3A expression is reduced by specific miRNAs important for endothelial function.

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Yasmeen, S., Kaur, S., Mirza, A.H. et al. miRNA-27a-3p and miRNA-222-3p as Novel Modulators of Phosphodiesterase 3a (PDE3A) in Cerebral Microvascular Endothelial Cells. Mol Neurobiol 56, 5304–5314 (2019). https://doi.org/10.1007/s12035-018-1446-5

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