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. 2013 Aug;123(8):3378-82.
doi: 10.1172/JCI67383. Epub 2013 Jul 15.

Atrial natriuretic peptide is negatively regulated by microRNA-425

Pankaj Arora  1 , Connie Wu, Abigail May Khan, Donald B Bloch, Brandi N Davis-Dusenbery, Anahita Ghorbani, Ester Spagnolli, Andrew Martinez, Allicia Ryan, Laurel T Tainsh, Samuel Kim, Jian Rong, Tianxiao Huan, Jane E Freedman, Daniel Levy, Karen K Miller, Akiko Hata, Federica Del Monte, Sara Vandenwijngaert, Melissa Swinnen, Stefan Janssens, Tara M Holmes, Emmanuel S Buys, Kenneth D Bloch, Christopher Newton-Cheh, Thomas J Wang
Affiliations

Atrial natriuretic peptide is negatively regulated by microRNA-425

Pankaj Arora et al. J Clin Invest. 2013 Aug.

Abstract

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.

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Figures

Figure 1
Figure 1. The effect of genotype and dietary sodium on plasma Nt-proANP levels during saline challenge is shown after 1 week of a (A) low-salt diet or (B) high-salt diet (P = 0.018 for genotype effect, P < 0.001 for diet and saline effects).
Samples for measurement of plasma Nt-proANP levels were obtained at baseline and hourly for 8 hours after the start of saline infusion. AA, rs5068 major homozygote; AG, rs5068 heterozygote.
Figure 2
Figure 2. Allele-specific effects of miR-425, anti–miR-425, and a modified miR-425 on luciferase activity encoded by firefly luciferase-NPPA 3′UTR constructs.
The ratio of firefly luciferase activity to renilla luciferase activity was normalized to that in cells transfected with a plasmid directing expression of luciferase without the NPPA 3′UTR (relative luciferase activity). Data are expressed as mean ± SEM (n = 6). Each experiment was repeated 3 times with similar results. (A) miR-425 reduces activity of the NPPA major-LUC construct but not the NPPA minor-LUC construct. (B) Anti–miR-425 increases activity of the NPPA major-LUC construct but not the NPPA minor-LUC construct. (C) A modified miR-425 targeting the NPPA 3′UTR minor allele reduces activity of the NPPA minor-LUC construct but not the NPPA major-LUC construct.
Figure 3
Figure 3. miR-425 transfection reduces NPPA mRNA levels and secretion of Nt-proANP immunoreactivity in human cardiomyocytes derived from induced pluripotent stem cells.
Cardiomyocytes (~4 × 105 per well) were transfected with miR-425 or a control miRNA. Twenty-four hours later, cells were washed and incubated in 1 ml of media. After an additional 48 hours, cells and media were harvested. (A) NPPA mRNA levels relative to those in cells transfected with control miRNA. (B) Concentrations of Nt-proANP immunoreactivity in the cell supernatant. Data are expressed as mean ± SEM (n = 4).
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