Open Accessp53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart failure
Author(s) -
ChihYang Huang,
PeiYing Pai,
ChiaHua Kuo,
TsungJung Ho,
Jingying Lin,
Ding-Yu Lin,
FuJen Tsai,
Viswanadha Vijaya Padma,
WeiWen Kuo
Publication year - 2017
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/cddis.2017.320
Subject(s) - heart failure , angiotensin ii , medicine , muscle hypertrophy , heat shock , myocyte , dilated cardiomyopathy , downregulation and upregulation , cardiology , endocrinology , biology , heat shock protein , gene , receptor , biochemistry
Hypertension-induced cardiac hypertrophy and attenuated cardiac function are the major characteristics of early stage heart failure. Cardiomyocyte death in pathological cardiac conditions is the primary cause of heart failure and mortality. Our previous studies found that heat shock factor 1 (HSF1) protected cardiomyocytes from death by suppressing the IGF-IIR signaling pathway, which is critical for hypertensive angiotensin II-induced cardiomyocyte apoptosis. However, the role of heat shock factor 2 (HSF2) in hypertension-induced cardiac hypertrophy is unknown. We identified HSF2 as a miR-18 target for cardiac hypertrophy. p53 activation in angiotensin II (ANG II)-stimulated NRVMs is responsible for miR-18 downregulation both i n vitro and in vivo , which triggers HSF2 expression and the activation of IGF-IIR-induced cardiomyocyte hypertrophy. Finally, we provide genetic evidence that miR-18 is required for cardiomyocyte functions in the heart based on the gene transfer of cardiac-specific miR-18 via adenovirus-associated virus 2 (AAV2). Transgenic overexpression of miR-18 in cardiomyocytes is sufficient to protect against dilated cardiomyopathy during hypertension-induced heart failure. Our results demonstrated that the p53-miR-18-HSF2-IGF-IIR axis was a critical regulatory pathway of cardiomyocyte hypertrophy in vitro and in vivo , suggesting that miR-18 could be a therapeutic target for the control of cardiac functions and the alleviation of cardiomyopathy during hypertension-induced heart failure.