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Restored autophagy is protective against PAK3-induced cardiac dysfunction

Andrea Ruiz-Velasco1, Rida Raja1, Xinyi Chen1

  • 1Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Iscience
|June 16, 2023
PubMed

Insights

Heart failure is a leading cause of death. This study reveals p21-activated kinase 3 (PAK3) worsens heart failure by suppressing autophagy, offering a new therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Heart failure remains a major global health challenge with limited effective treatments.
  • P21-activated kinase 3 (PAK3) has been identified as upregulated in failing hearts.
  • The precise role of PAK3 in cardiac pathophysiology is not fully understood.

Purpose of the Study:

  • To investigate the role of PAK3 in the progression of heart failure.
  • To elucidate the molecular mechanisms by which PAK3 affects cardiac function.
  • To explore the therapeutic potential of targeting the PAK3-autophagy axis in heart failure.

Main Methods:

  • Cardiac-specific PAK3 overexpression in mouse models.
  • Assessment of cardiac function and pathological remodeling.
  • Investigation of autophagy regulation in cardiomyocytes and human samples.
  • Pharmacological intervention with an autophagic inducer.

Main Results:

  • Cardiac-specific PAK3 overexpression led to exacerbated cardiac dysfunction, hypertrophy, fibrosis, and apoptosis.
  • PAK3 was found to suppress autophagy by hyper-activating mTORC1.
  • Inhibition of PAK3-mediated autophagy suppression improved cardiac function in vivo.
  • Targeting the PAK3-autophagy pathway demonstrated therapeutic efficacy.

Conclusions:

  • PAK3 plays a critical role in promoting heart failure progression by inhibiting myocardial autophagy.
  • PAK3 acts as a negative regulator of autophagy via mTORC1 signaling.
  • Modulating the PAK3-autophagy axis represents a promising therapeutic strategy for heart failure.
Keywords:
Cell biologyMolecular biologyOmics

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