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1 OUHSC, Oklahoma City, Oklahoma, United States
* To whom correspondence should be addressed. E-mail: david-kem{at}ouhsc.edu.
Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G-protein receptor kinase 2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 hours after coronary artery ligation (CAL) in the dog. We previously demonstrated the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1-hr prior to onset of ischemia; and this was associated with significant cardio-protection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine if a clinical window exists following the onset of ischemia for such a protective effect. Treatment of 6 dogs with the selective proteasome inhibitor bortezomib 1-hr after surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against loss of GRK2 at 24-hrs. There was no significant increase of Hsp70(72) in the EBZ of bortezomib treated animals compared to control. There was a striking absence of rapid (>300 bpm) and very rapid (>360 bpm) ventricular triplets that are highly predictive of sudden cardiac deaths (SCD) during EKG monitoring of the first 24 hrs in the bortezomib treated animals in contrast to non-treated infarcted animals. There were no SCDs in the 6 treated animals (0%) and five SCDs in the 14 control animals (36%). Assay of whole blood proteasome activity demonstrated the expected decrease over the 24-hr observation period. These data support the concept that proteasome treatment within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.
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