We previously identified a novel endogenous substance,
serofendic acid, from a lipophilic extract of
fetal calf serum. The compound, a low-molecular-weight
sulfur-containing atisane-type
diterpenoid, exhibited potent protective action against neurotoxicity induced by
glutamate,
nitric oxide, and
oxidant stress. We investigated whether this substance has a cardioprotective effect. Primary cultures of neonatal rat cardiac myocytes were exposed to
oxidant stress (H2O2) to induce cell death. Pretreatment with
serofendic acid significantly suppressed cell death induced by H2O2, and the cytoprotective effect was closely associated with the preservation of mitochondrial function.
Serofendic acid inhibited H2O2-induced loss of mitochondrial membrane potential in a concentration-dependent manner (with saturation by 100 microM), by attenuating matrix
calcium overload and intracellular accumulation of
reactive oxygen species. The protective effect of
serofendic acid was comparable to that of a mitochondrial
ATP-sensitive
potassium (
mitoK ATP) channel opener,
diazoxide. Furthermore,
mitoK ATP channel blocker,
5-hydroxydecanoate, abolished the protective effect of
serofendic acid.
Serofendic acid and
diazoxide, administered together, at 100 microM each, had no additive effects. Thus,
serofendic acid inhibited the
oxidant-induced mitochondrial death pathway, presumably through activation of the
mitoK(ATP) channel. In conclusion,
serofendic acid appears to protect cardiac myocytes from
oxidant-induced cell death by preserving the functional integrity of mitochondria. Our findings suggest that
serofendic acid may represent a novel candidate for cardioprotective
therapy in
ischemia/reperfusion injury.