Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production

Abstract

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.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01114-15.

ACKNOWLEDGMENTS

This study was supported by funds of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital; award number T32HL007208 from the National Heart, Lung, and Blood Institute (C.W.); the Howard Hughes Medical Institute (P.J.); grant support PF10/014 by KU Leuven (S.T. and S.P.J.); the Leducq Foundation (C.W., K.D.B., and D.B.B.); and grants from the NIH (R01HL098283, T.J.W. and C.N.-C.; R01HL113933, C.N.-C.; and R01HL124262, C.N.-C.).

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

None of the authors report any significant relationships with industry or financial disclosures related to the manuscript. C. Wu, P. Arora, T. J. Wang, K. D. Bloch, and C. Newton-Cheh are named as coinventors on a patent application relating to the use of miRNA antagonists to increase ANP production to treat hypertension and heart failure.

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Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.