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

• Published in: American journal of physiology. Heart and circulatory physiology 2007-12, Vol.293 (6), p.H3348-H3355
• Main Authors: Hadzimichalis, Norell M, Baliga, Sunanda S, Golfetti, Roseli, Jaques, Kathryn M, Firestein, Bonnie L, Merrill, Gary F
• Format: Article
• Language: English
• Subjects: Acetaminophen - pharmacology; Acetaminophen - therapeutic use; Analgesics; Animals; Apoptosis; Apoptosis - drug effects; Cardiology; Cardiovascular Agents - pharmacology; Cardiovascular Agents - therapeutic use; Cardiovascular system; Cell Separation; Cells; Cytochromes c - metabolism; Flow Cytometry; Guinea Pigs; Heart; Hemodynamics - drug effects; In Vitro Techniques; Male; Microscopy, Electron; Mitochondria, Heart - drug effects; Mitochondria, Heart - enzymology; Mitochondria, Heart - metabolism; Mitochondria, Heart - ultrastructure; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Swelling - drug effects; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - ultrastructure; Time Factors
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00947.2007

Department of Cell Biology and Neuroscience, Division of Life Sciences, Rutgers University, Piscataway, New Jersey Submitted 15 August 2007 ; accepted in final form 5 October 2007 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 cytochrome c 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. mitochondrial swelling; apoptosis; cytochrome c ; myocardial ischemia/reperfusion Address for reprint requests and other correspondence: G. F. Merrill, 604 Allison Road, Piscataway, NJ 08854 (e-mail: Merrill{at}biology.rutgers.edu )