TY - JOUR
T1 - Atrial natriuretic peptide is negatively regulated by microRNA-425
AU - Arora, Pankaj
AU - Wu, Connie
AU - May Khan, Abigail
AU - Bloch, Donald B.
AU - Davis-Dusenbery, Brandi N.
AU - Ghorbani, Anahita
AU - Spagnolli, Ester
AU - Martinez, Andrew
AU - Ryan, Allicia
AU - Tainsh, Laurel T.
AU - Kim, Samuel
AU - Rong, Jian
AU - Huan, Tianxiao
AU - Freedman, Jane E.
AU - Levy, Daniel
AU - Miller, Karen K.
AU - Hata, Akiko
AU - Del Monte, Federica
AU - Vandenwijngaert, Sara
AU - Swinnen, Melissa
AU - Janssens, Stefan
AU - Holmes, Tara M.
AU - Buys, Emmanuel S.
AU - Bloch, Kenneth D.
AU - Newton-Cheh, Christopher
AU - Wang, Thomas J.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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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U2 - 10.1172/JCI67383
DO - 10.1172/JCI67383
M3 - Article
C2 - 23867623
AN - SCOPUS:84881238374
SN - 0021-9738
VL - 123
SP - 3378
EP - 3382
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -