Biochemical events associated with rapid cellular damage during the oxygen- and calcium-paradoxes of the mammalian heart.
The O2- and Ca2(+)-paradoxes have a number of features in common and it is suggested that release of cytosolic proteins in both paradoxes is initiated by the activation of a sarcolemma NAD(P)H dehydrogenase which can generate a transmembrane flow of H+ and e- and also oxygen radicals or redox cycling which damage ion channels and membrane proteins (phase I). Entry of Ca2+ through the damaged ion channels then exacerbates the damage by further activating this system, either directly or indirectly, and the redox cycling and/or oxygen radicals cause further damage to integral and cytoskeletal proteins of the sarcolemma resulting in microdamage to the integrity of the membrane (phase II) and the consequent release or exocytosis of cytoplasmic proteins and, under specialised conditions, the blebbing of the sarcolemma. The system may be primed either by removal of extracellular Ca2+ or by raising [Ca2+]i by a variety of measures, these two actions being synergistic. The system is initially activated in the Ca2(+)-paradox by the membrane perturbation associated with removal of extracellular Ca2+; prolonged anoxia in the metabolically active cardiac muscle causes a depletion of the ATP supply, particularly in the absence of glucose, and hence a rise in [Ca2+]i in phase I of the oxygen paradox with the consequent activation of the NAD(P)H oxidase at the sarcolemma. Oxygen radicals are probably generated in both paradoxes and may have a partial role in the genesis of damage, but are not essential in the Ca2(+)-paradox which continues under anoxia. Massive entry of Ca2+ also activates an intracellularly localised dehydrogenase (probably at the SR) which produces myofilament damage by redox cycling.
Department of Zoology, University of Liverpool, England.
C J
CJ
Duncan
D000818:Animals; D002118:Calcium / Q000008:administration & dosage / Q000502:physiology*; D003402:Creatine Kinase / Q000378:metabolism; D005609:Free Radicals; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D009245:NADH Dehydrogenase / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism
D005609:Free Radicals; D011506:Proteins; D009252:NADPH Dehydrogenase; D009245:NADH Dehydrogenase; D003402:Creatine Kinase; D010100:Oxygen; D002118:Calcium