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Kruppel-like factor 4 protein regulates isoproterenol-induced cardiac hypertrophy by modulating myocardin expression

Tadashi Yoshida1, Maho Yamashita1, Chihiro Horimai1

  • 1Apheresis and Dialysis Center, School of Medicine, Keio University, Tokyo 160-8582, Japan.

The Journal of Biological Chemistry
|August 8, 2014
PubMed

Insights

Kruppel-like factor 4 (KLF4) normally protects against cardiac hypertrophy. Its absence in heart cells accelerates this condition by increasing cardiomyocyte size and fetal gene expression via myocardin regulation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Gene Regulation

Background:

  • Kruppel-like factor 4 (KLF4) is known for its role in vascular diseases.
  • Its function in cardiac disease, particularly cardiac hypertrophy, remains largely undetermined.
  • KLF4 is expressed in cardiac cells, suggesting potential roles in heart function.

Purpose of the Study:

  • To investigate the role of KLF4 in the development of cardiac hypertrophy.
  • To elucidate the molecular mechanisms by which KLF4 influences cardiac hypertrophy.
  • To determine if KLF4 mediates the effects of certain therapeutic agents on cardiac hypertrophy.

Main Methods:

  • Generation of cardiomyocyte-specific Klf4 knockout (CM Klf4 KO) mice using Cre/LoxP technology.
  • Induction of cardiac hypertrophy via chronic isoproterenol (ISO) infusion.
  • Analysis of cardiac morphology, cardiomyocyte size, fetal gene expression (e.g., Nppa), and myocardin levels.

Main Results:

  • ISO-induced cardiac hypertrophy was significantly enhanced in CM Klf4 KO mice compared to controls.
  • CM Klf4 KO mice exhibited increased cardiomyocyte size and elevated expression of fetal cardiac genes like Nppa.
  • KLF4 was found to regulate Nppa expression by modulating myocardin expression and activity.
  • KLF4 mediated the antihypertrophic effect of trichostatin A, but not olmesartan.

Conclusions:

  • KLF4 acts as a crucial regulator of cardiac hypertrophy.
  • KLF4 modulates cardiac hypertrophy by controlling myocardin expression and activity.
  • These findings reveal a novel mechanism underlying cardiac hypertrophy and suggest KLF4 as a potential therapeutic target.

Keywords:
Adrenergic ReceptorAngiotensin IICardiac HypertrophyNatriuretic PeptideSerum Response FactorTranscription Factor

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