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TGF‐β regulated miRNAs: therapeutic targets for cardiac hypertrophy
Author(s) -
Yang Xiao,
Wang Jian
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.835.15
Subject(s) - microrna , muscle hypertrophy , pressure overload , smad , heart failure , downregulation and upregulation , cardiac fibrosis , gene silencing , transforming growth factor , cardiac function curve , fibrosis , medicine , endogeny , genetically modified mouse , transgene , biology , endocrinology , cardiac hypertrophy , gene , genetics
Heart failure (HF) is one of the most frequent causes of death worldwide. The underlying causes of HF are diverse but often relate to cardiac hypertrophy. The role of TGF‐β signaling in cardiac hypertrophy has been extremely contradictory. We have previously showed that targeted deletion of Smad4 unexpectedly leads to cardiac hypertrophy, demonstrating that the endogenous cardiomyocyte Smad4‐dependent TGF‐β pathway protects heart from cardiac hypertrophy and fibrosis. Recently, we have revealed that the function of endogenous TGF‐β/Smad signaling in maintaining cardiac homeostasis involves the downregulation of miRNAs inducing cardiac hypertrophy. We show that TGF‐β1 inhibits the expression of miR‐23a/miR‐27a/miR‐24–2 and miR‐23b/miR‐27b/miR‐24–1 clusters at the transcriptional level. Transgenic mice with cardiomyocyte‐specific overexpression of miR‐27b exhibit cardiac hypertrophy and dysfunction by directly targeting PPAR‐¦Ã. Most importantly, in vivo silencing of miR‐27b in a pressure‐overload‐induced mouse model of HF attenuates cardiac hypertrophy and dysfunction. The function and mechanisms of other miRNAs regulated by TGF‐β/Smad signaling in cardiac hypertrophy have also been investigated. All these results provide critical genetic evidence showing that TGF‐β‐regulated miRNAs might serve as efficient therapeutic targets for cardiac diseases.