Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production
| Autor: | Daniel I. Nathan, Daniel Bloch, Olle Melander, Dongjian Hu, Pankaj Arora, Stefan Janssens, Kenneth D. Bloch, Thomas J. Wang, Connie Wu, Kaitlin Allen, Pawina Jiramongkolchai, Liam A. Hurst, Emmanuel S. Buys, Obiajulu Agha, Christopher Newton-Cheh, Ibrahim J. Domian, J. Gustav Smith, Sander Trenson |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Placenta Down-Regulation Blood Pressure 030204 cardiovascular system & hematology Biology 03 medical and health sciences 0302 clinical medicine Atrial natriuretic peptide Downregulation and upregulation Pregnancy microRNA Humans Myocytes Cardiac Allele Molecular Biology Gene Alleles Cells Cultured Genetic association Genetics Messenger RNA Genetic Variation Cell Biology Articles Cell biology Minor allele frequency MicroRNAs 030104 developmental biology Female Atrial Natriuretic Factor |
| Zdroj: | Molecular and Cellular Biology |
| ISSN: | 1098-5549 |
| Popis: | Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure. |
| Databáze: | OpenAIRE |
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