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Inhibition of cGMP Degradation contributes to the Cardioprotective Effect of Resveratrol on Ischemia/Reperfusion Injury
Author(s) -
Xi Jinkun,
Fei Shuo,
Xu Zhelong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1049.3
Subject(s) - resveratrol , cardioprotection , chemistry , phosphodiesterase , pharmacology , reperfusion injury , pde10a , mitochondrial permeability transition pore , ibmx , cgmp dependent protein kinase , cgmp specific phosphodiesterase type 5 , phosphorylation , intracellular , phosphodiesterase 3 , mptp , protein kinase a , biochemistry , ischemia , medicine , endocrinology , sildenafil , apoptosis , biology , enzyme , programmed cell death , in vitro , mitogen activated protein kinase kinase , dopamine , forskolin , dopaminergic
Resveratrol is cardioprotective and our previous study demonstrated that resveratrol prevents reperfusion injury by targeting mitochondrial permeability transition pore (mPTP) throughthe cGMP/PKG signaling pathway. Nevertheless, the exact mechanism by which resveratrol activates the cGMP/PKG pathway remains unclear. The cGMP level is regulated by both guanylyl cyclase that promotes the synthesis of cGMP using NO and phosphodiesterase (PDE)which induces the hydrolysis of cGMP. We aimed to explore the mechanism by which resveratrol increases cGMP leading cardioprotection, focusing on the roles of NO and PDE5. Exposure of rat cardiomyocytes to 10 µM resveratrol for 10 min did not show an increase in DAF‐FM fluorescence , indicating that resveratrol does not produce NO. In contrast, resveratrol reduced PDE5 activity and increased cGMP levels at reperfusion in the heart, indicating that the cardioprotective effect of resveratrol is not mediated by guanylyl cyclase but is dependent on PDE5. The non‐selective PDE inhibitor IBMX given at reperfusion could mimic the cardioprotective effect of resveratrol by reducing infarct size in isolated rat hearts, an effect that was reversed by mPTP opener atractyloside, indicating that resveratrol modulate the mPTP opening through inhibition of PDE. In addition, resveratrol enhanced the phosphorylation of VASPand GSK‐3β, an effect that was partially blocked by PKG inhibitor KT5823. In conclusion, these data suggest that inhibition of PDE5 leading to the increase in intracellular cGMP, which accounts for the cardioprotective effect of resveratrol on reperfusion injury through prevention of the mPTP opening via the cGMP/PKG/GSK‐3β signal pathway.