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p53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart

Chih-Yang Huang1, Pei-Ying Pai2, Chia-Hua Kuo3

  • 1Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Cell Death & Disease
|August 11, 2017
PubMed

Insights

Heat shock factor 2 (HSF2) drives cardiac hypertrophy via the miR-18/IGF-IIR pathway in hypertension. Restoring miR-18 protects against heart failure and cardiomyopathy.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Hypertension causes cardiac hypertrophy and heart failure, often due to cardiomyocyte apoptosis.
  • Heat shock factor 1 (HSF1) protects cardiomyocytes by suppressing the IGF-IIR pathway in response to angiotensin II.
  • The role of heat shock factor 2 (HSF2) in hypertension-induced cardiac hypertrophy remains unclear.

Purpose of the Study:

  • To investigate the role of HSF2 in hypertension-induced cardiac hypertrophy.
  • To elucidate the regulatory pathway involving miR-18, HSF2, and IGF-IIR in cardiomyocyte hypertrophy.
  • To assess the therapeutic potential of miR-18 in mitigating hypertension-induced heart failure.

Main Methods:

  • Identified HSF2 as a target of miR-18 in cardiac hypertrophy.
  • Investigated the p53-mediated downregulation of miR-18 in angiotensin II-stimulated cells (in vitro) and in vivo.
  • Utilized cardiac-specific gene transfer with adenovirus-associated virus 2 (AAV2) to overexpress miR-18 in cardiomyocytes.

Main Results:

  • p53 activation downregulates miR-18, leading to increased HSF2 expression and IGF-IIR-mediated cardiomyocyte hypertrophy.
  • Genetic evidence confirmed miR-18's requirement for cardiomyocyte function.
  • Transgenic overexpression of miR-18 protected against dilated cardiomyopathy in a hypertension model.

Conclusions:

  • The p53-miR-18-HSF2-IGF-IIR axis is a critical regulator of cardiomyocyte hypertrophy.
  • miR-18 acts as a protective factor against hypertension-induced cardiac dysfunction.
  • miR-18 represents a potential therapeutic target for managing cardiomyopathy and heart failure.

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