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Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells

Emma L Wilkinson1, James E Sidaway1, Michael J Cross1

  • 1Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Journal of Cellular Physiology
|June 23, 2017
PubMed

Insights

Statins activate ERK5 signaling in heart cells, strengthening tight junctions and reducing permeability. This ERK5 activation may explain statins' protective effects against doxorubicin-induced heart damage.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Endothelial Cell Function

Background:

  • The MEKK3/MEK5/ERK5 pathway is crucial for cardiovascular development.
  • The role of ERK5 in cardiac endothelial cells and its modulation by statins is not fully understood.

Purpose of the Study:

  • To investigate the physiological role of ERK5 in cardiac endothelial cells.
  • To determine the effects of statin drugs on ERK5 activation and endothelial cell permeability.

Main Methods:

  • Utilized human cardiac microvascular endothelial cells (HCMECs).
  • Manipulated ERK5 expression via siRNA and gene overexpression.
  • Assessed tight junction formation and cell permeability.
  • Examined ERK5 activation and localization upon statin treatment.

Main Results:

  • ERK5 regulates endothelial tight junction formation and cell permeability.
  • Statin treatment activated ERK5, promoting its translocation to the plasma membrane and co-localization with ZO-1.
  • Statins reduced endothelial cell permeability by inhibiting HMG-CoA reductase and isoprenoid synthesis.
  • Statin pretreatment protected against doxorubicin-induced disruption of tight junctions and increased permeability.

Conclusions:

  • ERK5 plays a key role in regulating endothelial tight junction formation and permeability.
  • Statin-induced ERK5 activation decreases cardiac endothelial cell permeability.
  • This mechanism may contribute to the cardioprotective effects of statins, particularly in mitigating doxorubicin-induced cardiotoxicity.

Keywords:
ERK5ZO-1cardiotoxicitypermeabilitystatin

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