Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Strategies for maximizing recovery of salvageable post-ischemic myocardium include, a) Tissue modification prior to reperfusion, b) Minimizing adverse effects with 'tailored' reperfusion, and finally c) Repairing the effects of reperfusion injury.

We propose to assess a mechanism of myocardial reperfusion injury involving the oxidation of thiol groups on key enzymes. H2O2 will be targeted as the molecule responsible for this oxidant stress. It is neutral, freely permeable, and is the nexus in the evolution of toxic oxygen metabolites (TOM) during reperfusion. One pivotal enzyme vulnerable to TOM damage is creatine kinase (CK). One isoenzyme (CKmito) converts mitochondrially produced ATP into diffusible high energy as phosphocreatine (PCr). Other cytosolic CK isoenzymes (CKcyto) associated with energy utilizing termini use PCr to maintain local ATP levels. Following ischemia, the rapid recovery of PCr levels during early reperfusion indicates that mitochondrial production of ATP and its rapid conversion to PCr by CKmito is relatively unimpaired. The slower recovery of cellular ATP and function may implicate a failure of the cytosolic CKs to regenerate ATP from PCr at energy utilizing sites. With continued reperfusion after 'reversible injury' PCr/ATP ratios return to normal, concurrent with improvements in cardiac function.

Using a multidisciplinary approach we will interrelate function, bioenergetic profile (P-31NMR), and myocardial CK isozyme contents (gel electrophoresis) during ischemia, and throughout reperfusion. The purposes of this study are to (1) Assess the differential sensitivity of CKmito vd CKcyto (by gel electrophoresis) following exposure to H2O2 in vitro. (2) Relate the severity of the reperfusion injury to differential depressions in CK isozyme activity in vivo. (3) Characterize parallel improvements in the activity of each CK Isozyme with function and bioenergetics during reperfusion. (4) Explore the H2O2 impairment of CK isozymes in vivo as a specific thiol oxidative mechanism for toxic oxygen metabolites (TOMs) in reperfusion injury.

Exploiting creatine kinase as the molecular nexus between TOMs, high energy metabolism, and myocardial function, should prove invaluable in the design of practical therapies.
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