Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway

Abstract

Our laboratory has previously reported that acetaminophen confers functional cardioprotection following cardiac insult, including ischemia/reperfusion, hypoxia/reoxygenation, and exogenous peroxynitrite administration. In the present study, we further examined the mechanism of acetaminophen-mediated cardioprotection following ischemia/reperfusion injury. Langendorff-perfused guinea pig hearts were exposed to acute treatment with acetaminophen (0.35 mM) or vehicle beginning at 15 min of a 30-min baseline stabilization period. Low-flow global myocardial ischemia was subsequently induced for 30 min followed by 60 min of reperfusion. At the completion of reperfusion, hearts were homogenized and separated into cytosolic and mitochondrial fractions. Mitochondrial swelling and mitochondrial cytochromec release were assessed and found to be significantly and completely reduced in acetaminophen- vs. vehicle-treated hearts following reperfusion. In a separate group of hearts, ventricular myocytes were isolated and subjected to fluorescence-activated cell sorting. Acetaminophen-treated hearts showed a significant decrease in late stage apoptotic myocytes compared with vehicle-treated hearts following injury (58 +/- 1 vs. 81 +/- 5%, respectively). These data, together with electron micrograph analysis, suggest that acetaminophen mediates cardioprotection, in part, via inhibition of the mitochondrial permeability transition pore and subsequent apoptotic pathway.

SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury

“…We observed that SDF-1 did not decrease LDH levels compared with vehicle group, implying that SDF-1-improved cardiac function is unlikely through reduction of necrotic cell death. Being consistent with our findings, more and more recent studies (13,16,31) have demonstrated that decreasing apoptosis and apoptotic signaling are able to protect I/R-induced cardiac dysfunction by using a Langendorff model.…”

Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3β and mitochondrial permeability transition pore

“…Since the mitochondrial permeability transition pore (mPTP) opening plays a critical role in the pathogenesis of reperfusion injury, it is possible that resveratrol prevents reperfusion injury by inhibiting the pore opening. Therefore, we then determined if resveratrol could prevent the mPTP opening by detecting changes in light absorbance (Hadzimichalis et al, 2007). As shown in Fig.…”

Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain

“…The current model is that ApAP protects the heart against myocardial infarction via inhibition of the mitochondrial permeability transition pore and consequent cell death (Hadzimichalis et al , 2007). However, the mechanism of action of ApAP remains unknown.…”