Isoespintanol, a monoterpene isolated from oxandra cf xylopioides, ameliorates the myocardial ischemia-reperfusion injury by AKT/PKCε/eNOS-dependent pathways
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To determine the actions of isoespintanol (Isoesp) on post-ischemic myocardial and mitochondrial alterations.
Hearts removed from Wistar rats were perfused by 20 min. After this period, the coronary flow was interrupted by half an hour and re-established during 1 h. In the treated group, Isoesp was administered at the beginning of reperfusion. To assess the participation of ε isoform of protein kinase C (PKCε), protein kinase B (PKB/Akt), and nitric oxide synthase (NOS), hearts were treated with Isoesp plus the respective inhibitors (chelerythrine, wortmannin, and N-nitro-l-arginine methyl ester). Cell death was determined by triphenyl tetrazolium chloride staining technique. Post-ischemic recovery of contractility, oxidative stress, and content of phosphorylated forms of PKCε, Akt, and eNOS were also examined. Mitochondrial state was assessed through the measurement of calcium-mediated response, calcium retention capacity, and mitochondrial potential.
Isoesp limited cell death, decreased post-ischemic dysfunction and oxidative stress, improved mitochondrial state, and increased the expression of PKCε, Akt, and eNOS phosphorylated. All these beneficial effects achieved by Isoesp were annulled by the inhibitors.
These findings suggest that activation of Akt/eNOS and PKCε signaling pathways are involved in the development of Isoesp-induced cardiac and mitochondria tolerance to ischemia-reperfusion.
KeywordsIsoespintanol Ischemia-reperfusion Infarct size Akt PKCε eNOS
Nitric oxide synthase
l-NG-Nitroarginine methyl ester
Protein kinase C ε
Protein kinase B
Coronary perfusion pressure
Thiobarbituric acid reactive substances
Light scattering decrease
Ca2+ retention capacity
Mitochondrial membrane potential
Mitochondrial permeability transition pore
Left ventricular developed pressure
Maximal velocity of rise of left ventricular pressure
Left ventricular end diastolic pressure
Glyceraldehyde 3-phosphate dehydrogenase
Radical oxygen species
L.G.A. performed the western blots; A.C.P. performed the mitochondrial experiments; J.F. performed the isolated hearts experiments; B.J. isolated and provided the drug; G.Sch. contributed to the conception of the study; S.M. wrote the manuscript. All the authors contributed to the analysis and interpretation of data, critically reviewed, and approved the final draft.
This work was supported by the Grant M-203 from the National University of La Plata, Argentina, to Dr. S. Mosca.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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