Cell Death and Adenosine Triphosphate

apoptotic pathway can partially prevent the deleterious ef- fects of long-term ischemia by reducing the rate of apoptosis. In addition, these authors show that "infarct size" was reduced in treated hearts and that the rate of polymorphonu- clear cell infiltration was minimal as compared with hearts without gene transfer. Infarct size was determined in Lange- ndorff buffer-perfused hearts without any coronary artery ligation and describes the tissue area with necrotic cells as demonstrated by triphenyltetrazolium (TTC) staining. To the uninitiated reader it appears, therefore, that an intervention aimed at reducing apoptosis is also able to interfere with the process of ischemic cell death, ie, with oncosis (this is the preferred, modern term for necrosis; necrosis proper is the process of cell demise after any type of cell death4). The number of cardiomyo- cytes dying by either cell death mechanism, apoptotic or oncotic, was reduced: Only 6.5% of all cardiomyocytes were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) positive in hearts with Bcl-xL gene transfer, as compared with 18.9% in the untreated hearts, and infarct size was 23% in the treated group versus 47.7% in the hearts without gene transfer. Creatine kinase (CK) activity measured in the coronary outflow of Langendorff-perfused hearts was likewise reduced in hearts with Bcl-xL gene transfer. See p7 6 The cell death paradox is here represented by the astound- ing phenomenon that apparently 2 modes of cell death, apoptotic and oncotic, were influenced by Bcl-xL gene transfer, which should exclusively interfere with the apoptotic pathway. This is surprising given the well-known fact that both modes of cell death employ different mechanisms of initiation and cellular execution.5 Apoptosis is a prepro- grammed (suicidal), mostly caspase-driven and energy- dependent process, whereas oncotic cell death is accidental (because ischemic injury is not preprogrammed), is indepen- dent of caspase activation, and occurs subsequent to ATP depletion.6 In addition, a third type of cellular demise has been described, autophagic cell death, but this may not be of great importance in the present animal model because it occurs mostly in tissue exhibiting chronic degeneration, such as Alzheimer's disease in the brain and failure of the human heart.7,8