Upregulation of cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid inhibits apoptosis in neonatal rat cardiomyocytes by a caspase-dependent pathway

Cytokine. 2012 Nov;60(2):360-8. doi: 10.1016/j.cyto.2012.04.029. Epub 2012 Jun 18.


Short, nonlethal ischemic episodes administered to hearts directly after ischemic events (ischemic postconditioning, IPost) have an advantage over ischemic preconditioning (IPC). The endogenous cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid (CYP2J3/11,12-EET) is upregulated by IPost, but not IPC, in the rat heart. The CYP epoxygenase inhibitor N-methylsulphonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH) reduces the cardioprotective effects of IPost, but not IPC. We proposed that upregulation of CYP2J3/11,12-EET during IPost induces cardioprotection by inhibiting cardiomyocyte apoptosis and that multiple apoptotic signals, including changes in mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening, mitochondrial cytochrome c leakage, caspase-3 levels, and levels of protective kinases such as Bcl-2 and Bax, are involved in the process. Neonatal rat cardiomyocytes underwent 3-h hypoxia followed by 2-, 5-, or 6-h reoxygenation (H/R) or three cycles of 5-min reoxygenation followed by 5-min hypoxia before 90-min reoxygenation (HPost); or were transfected with pcDNA3.1-CYP2J3 for 48 h before H/R; or were treated with MS-PPOH for 10 min before HPost. For HPost alone, pcDNA3.1-CYP2J3 transfection attenuated cardiomyocyte apoptosis to 68.4% (p<0.05) of that with H/R. pcDNA3.1-CYP2J3 transfection significantly decreased MMP and inhibited mPTP opening induced by H/R, reduced mitochondrial cytochrome c leakage, cleaved caspase-3 protein expression, and increased the ratio of Bcl-2 to Bax expression. MS-PPOH abolished this effect. Therefore, upregulation of CYP2J3/11,12-EET during HPost is involved in cardioprotection by inhibiting apoptosis via a caspase-dependent pathway, and the apoptosis-suppressive effect may have important clinical implications during HPost.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives*
  • 8,11,14-Eicosatrienoic Acid / metabolism
  • Amides / pharmacology
  • Animals
  • Animals, Newborn
  • Apoptosis* / drug effects
  • Caspase 3 / metabolism*
  • Cell Survival / drug effects
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochromes c / metabolism
  • Hypoxia / enzymology
  • Hypoxia / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology*
  • Oxygen / metabolism
  • Rats
  • Rats, Wistar
  • Up-Regulation* / drug effects
  • bcl-2-Associated X Protein / metabolism


  • Amides
  • Cytochrome P-450 Enzyme Inhibitors
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
  • bcl-2-Associated X Protein
  • 11,12-epoxy-5,8,14-eicosatrienoic acid
  • Cytochromes c
  • Cytochrome P-450 Enzyme System
  • Cyp2j3 protein, rat
  • Caspase 3
  • 8,11,14-Eicosatrienoic Acid
  • Oxygen