title: Regulation of the proteasome by ATP: implications for ischemic myocardial injury and donor heart preservation.
abstract: Several lines of evidence suggest that proteasomes are involved in multiple aspects of myocardial physiology and pathology, including myocardial ischemia-reperfusion injury. It is well established that the 26S proteasome is an ATP-dependent enzyme and that ischemic heart disease is associated with changes in the ATP content of the cardiomyocyte. A functional link between the 26S proteasome, myocardial ATP concentrations, and ischemic cardiac injury, however, has been suggested only recently. This review discusses the currently available data on the pathophysiological role of the cardiac proteasome during ischemia and reperfusion in the context of the cellular ATP content. Depletion of the myocardial ATP content during ischemia appears to activate the 26S proteasome via direct regulatory effects of ATP on 26S proteasome stability and activity. This implies pathological degradation of target proteins by the proteasome and could provide a pathophysiological basis for beneficial effects of proteasome inhibitors in various models of myocardial ischemia. In contrast to that in the ischemic heart, reduced and impaired proteasome activity is detectable in the postischemic heart. The paradoxical findings that proteasome inhibitors showed beneficial effects when administered during reperfusion in some studies could be explained by their anti-inflammatory and immune suppressive actions, leading to reduction of leukocyte-mediated myocardial reperfusion injury. The direct regulatory effects of ATP on the 26S proteasome have implications for the understanding of the contribution of the 26S proteasome to the pathophysiology of the ischemic heart and its possible role as a therapeutic target.
authors.affiliation: Departments of Surgery and Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL 60153, USA. mmajetschak@lumc.edu
authors.forename: Matthias
authors.initials: M
authors.lastname: Majetschak
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004795:Enzyme Stability; D016027:Heart Transplantation; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009926:Organ Preservation / Q000379:methods; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D014019:Tissue Donors
chemical_list: D061988:Proteasome Inhibitors; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: 20S proteasome; 26S proteasome; heart transplantation; myocardial infarction; protein degradation