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Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7.

Abstract：

RATIONALE:Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules. OBJECTIVES:We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)-induced cardiac hypertrophy. METHODS AND RESULTS:Microarray analyses of mature rodent microRNAs and quantitative RT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes therein. Adenovirus-mediated expression of miR-98 in cardiomyocytes reduced cell size both at baseline and in response to Ang II. Knockdown of miR-98, and of other members of the let-7 family, augmented Ang II-induced cardiac hypertrophy, and attenuated Trx1-mediated inhibition of Ang II-induced cardiac hypertrophy, suggesting that endogenous miR-98/let-7 mediates the antihypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. Ang II significantly upregulated cyclin D2, which in turn plays an essential role in mediating Ang II-induced cardiac hypertrophy, whereas overexpression of Trx1 inhibited Ang II-induced upregulation of cyclin D2. miR-98 decreased both expression of cyclin D2 and the activity of a cyclin D2 3'UTR luciferase reporter, suggesting that both Trx1 and miR-98 negatively regulate cyclin D2. Overexpression of cyclin D2 attenuated the suppression of Ang II-induced cardiac hypertrophy by miR-98, suggesting that the antihypertrophic actions of miR-98 are mediated in part by downregulation of cyclin D2. CONCLUSIONS:These results suggest that Trx1 upregulates expression of the let-7 family, including miR-98, which in turn inhibits cardiac hypertrophy, in part through downregulation of cyclin D2.

journal_name

Circ Res

journal_title

Circulation research

authors

Yang Y,Ago T,Zhai P,Abdellatif M,Sadoshima J

doi

10.1161/CIRCRESAHA.110.228437

subject

Has Abstract

pub_date

2011-02-04 00:00:00

pages

305-13

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.110.228437

journal_volume

108

pub_type

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Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7.