The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Effects of hydrogen peroxide on voltage-dependent K+ currents in human cardiac fibroblasts through protein kinase pathways

  • Bae, Hyemi (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Lee, Donghee (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Kim, Young-Won (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Choi, Jeongyoon (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Lee, Hong Jun (Biomedical Research Institute, College of Medicine, Chung-Ang University) ;
  • Kim, Sang-Wook (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Kim, Taeho (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Noh, Yun-Hee (Department of Biochemistry, School of Medicine, Konkuk University) ;
  • Ko, Jae-Hong (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Bang, Hyoweon (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Lim, Inja (Department of Physiology, College of Medicine, Chung-Ang University)
  • Received : 2016.03.08
  • Accepted : 2016.04.04
  • Published : 2016.05.01
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Abstract

Human cardiac fibroblasts (HCFs) have various voltage-dependent $K^+$ channels (VDKCs) that can induce apoptosis. Hydrogen peroxide ($H_2O_2$) modulates VDKCs and induces oxidative stress, which is the main contributor to cardiac injury and cardiac remodeling. We investigated whether $H_2O_2$ could modulate VDKCs in HCFs and induce cell injury through this process. In whole-cell mode patch-clamp recordings, application of $H_2O_2$ stimulated $Ca^{2+}-activated$ $K^+$ ($K_{Ca}$) currents but not delayed rectifier $K^+$ or transient outward $K^+$ currents, all of which are VDKCs. $H_2O_2-stimulated$ $K_{Ca}$ currents were blocked by iberiotoxin (IbTX, a large conductance $K_{Ca}$ blocker). The $H_2O_2-stimulating$ effect on large-conductance $K_{Ca}$ ($BK_{Ca}$) currents was also blocked by KT5823 (a protein kinase G inhibitor) and 1 H-[1, 2, 4] oxadiazolo-[4, 3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor). In addition, 8-bromo-cyclic guanosine 3', 5'-monophosphate (8-Br-cGMP) stimulated $BK_{Ca}$ currents. In contrast, KT5720 and H-89 (protein kinase A inhibitors) did not block the $H_2O_2-stimulating$ effect on $BK_{Ca}$ currents. Using RT-PCR and western blot analysis, three subtypes of $K_{Ca}$ channels were detected in HCFs: $BK_{Ca}$ channels, small-conductance $K_{Ca}$ ($SK_{Ca}$) channels, and intermediate-conductance $K_{Ca}$ ($IK_{Ca}$) channels. In the annexin V/propidium iodide assay, apoptotic changes in HCFs increased in response to $H_2O_2$, but IbTX decreased $H_2O_2$-induced apoptosis. These data suggest that among the VDKCs of HCFs, $H_2O_2$ only enhances $BK_{Ca}$ currents through the protein kinase G pathway but not the protein kinase A pathway, and is involved in cell injury through $BK_{Ca}$ channels.

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References

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