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J Cell Mol Med. 2019 Aug 29. doi: 10.1111/jcmm.14641. [Epub ahead of print]

Long non-coding RNA cardiac hypertrophy-associated regulator governs cardiac hypertrophy via regulating miR-20b and the downstream PTEN/AKT pathway.

Author information

1
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
2
Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
3
Center of Chronic Diseases and Drug Research of Mudanjiang Medical, University of Alliance of Sino-Russian Medical Universities, Mudanjiang Medical University, Mudanjiang, China.
4
Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, China.

Abstract

Pathological cardiac hypertrophy (CH) is a key factor leading to heart failure and ultimately sudden death. Long non-coding RNAs (lncRNAs) are emerging as a new player in gene regulation relevant to a wide spectrum of human disease including cardiac disorders. Here, we characterize the role of a specific lncRNA named cardiac hypertrophy-associated regulator (CHAR) in CH and delineate the underlying signalling pathway. CHAR was found markedly down-regulated in both in vivo mouse model of cardiac hypertrophy induced by pressure overload and in vitro cellular model of cardiomyocyte hypertrophy induced by angiotensin II (AngII) insult. CHAR down-regulation alone was sufficient to induce hypertrophic phenotypes in healthy mice and neonatal rat ventricular cells (NRVCs). Overexpression of CHAR reduced the hypertrophic responses. CHAR was found to act as a competitive endogenous RNA (ceRNA) to down-regulate miR-20b that we established as a pro-hypertrophic miRNA. We experimentally established phosphatase and tensin homolog (PTEN), an anti-hypertrophic signalling molecule, as a target gene for miR-20b. We found that miR-20b induced CH by directly repressing PTEN expression and indirectly increasing AKT activity. Moreover, CHAR overexpression mitigated the repression of PTEN and activation of AKT by miR-20b, and as such, it abrogated the deleterious effects of miR-20b on CH. Collectively, this study characterized a new lncRNA CHAR and unravelled a new pro-hypertrophic signalling pathway: lncRNA-CHAR/miR-20b/PTEN/AKT. The findings therefore should improve our understanding of the cellular functionality and pathophysiological role of lncRNAs in the heart.

KEYWORDS:

cardiac hypertrophy; cardiac hypertrophy-associated regulator; long non-coding RNA; miR-20b; phosphatase and tensin homolog

PMID:
31465630
DOI:
10.1111/jcmm.14641
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