In this work, we explored the protective effect of DT-018, a danshensu and tetramethylpyrazine conjugate,
on mitochondrial injury induced by tert-butylhydroperoxide (t-BHP) and its possible mechanisms of action.
DT-018 effectively quenched intracellular and mitochondrial reactive oxygen species (ROS), preserved the mitochondrial
function, restored the intracellular level of ATP and augmented mitochondrial membrane potential
(Δψm) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the
expression of MEF2D and PGC-1α as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and
PGC-1α-siRNA down-regulated the protein expression of PGC-1α and partially abolished the cardioprotection of
DT-018 in t-BHP injured cells. For the in vivo studies, administration of DT-018 significantly alleviated infarct
area induced by ischemia and reperfusion injury. These observations demonstrated that the cardioprotective effect
of DT-018 is mediated, at least in part, by preservation of mitochondrial integrity through up-regulation of
Keywords: Danshensu derivative, cardioprotection, mitochondrial function preservation, ischemia/reperfusion, MEF2D/PGC-1α pathway,
reactive oxygen species (ROS.
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