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Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac

M Shen1, L Wang2, B Wang2

  • 11] Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China [2] Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya, China.

Cell Death & Disease
|November 21, 2014
PubMed

Insights

Blocking volume-sensitive outward rectifying (VSOR) chloride channels reduces endoplasmic reticulum stress and improves cardiac function. This study identifies a novel therapeutic strategy for heart conditions linked to ER stress and reactive oxygen species.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Physiology

Background:

  • Endoplasmic reticulum (ER) stress contributes to cardiomyocyte apoptosis and cardiac contractile dysfunction (CCD).
  • The precise molecular mechanisms underlying ER stress-induced cardiac damage require further elucidation for therapeutic development.

Purpose of the Study:

  • To investigate the role of volume-sensitive outward rectifying (VSOR) chloride channels in tunicamycin-induced ER stress and cardiac dysfunction.
  • To explore the therapeutic potential of VSOR channel blockers in mitigating ER stress-related cardiac anomalies.

Main Methods:

  • Established a tunicamycin-induced model of cardiomyocyte ER stress.
  • Utilized DIDS and DCPIB to block VSOR Cl(-) channels.
  • Assessed ER stress markers (GRP78, eIF2α, ATF4, XBP1, CHOP), Wnt signaling, and cardiomyocyte function.

Main Results:

  • Tunicamycin induced ER stress, cardiomyocyte apoptosis, and cardiac contractile dysfunction.
  • Blockade of VSOR channels with DIDS or DCPIB ameliorated cardiac dysfunction and suppressed ER stress pathways.
  • VSOR channel activation was linked to increased reactive oxygen species (ROS) and involved the CHOP-Wnt pathway.

Conclusions:

  • The ROS/VSOR pathway plays a critical role in mediating ER stress and cardiac dysfunction via the CHOP-Wnt signaling axis.
  • VSOR chloride channel blockers demonstrate therapeutic potential for treating ER stress-associated cardiac disorders.

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