Submitted on August 15, 2007
Accepted on October 5, 2007
Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway
Norell Melissa Hadzimichalis1, Sunanda Subramanya Baliga1, Roseli Golfetti1, Kathryn M Jaques1, Bonnie L. Firestein1, and Gary F Merrill1*
1 Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, United States
* To whom correspondence should be addressed. E-mail: merrill{at}biology.rutgers.edu.
Our laboratory has previously reported that acetaminophen confers functional cardioprotection following cardiac insult, including ischemia/reperfusion, hypoxia/reoxygenation, and exogenous peroxynitrite administration. In the current 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 (0.35mM) or vehicle beginning at 15 minutes of a 30-minute baseline stabilization period. Low flow global myocardial ischemia was subsequently induced for 30 minutes followed by 60 minutes of reperfusion. At the completion of reperfusion, hearts were homogenized and separated into cytosolic and mitochondrial fractions. Mitochondrial swelling and mitochondrial cytochrome c release were assessed and found to be significantly and completely reduced in acetaminophen- versus 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 when compared to 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.
