Arrhythmia-prone subepicardial border zone (EBZ) tissue demonstrates decreased G-protein receptor kinase 2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 hours after coronary artery ligation (CAL) in the dog. Using a semiquantitative immunofluorescence technique, the relative fluorescence intensity (RF) of GRK2 in EBZ decreased to 24% of remote site (RS) (P < 0.01, n = 30 cells from 3 dogs) while GRK5 RF did not change. Confocal studies of cardiac tissue from transgenic mice overexpressing GRK2 validated use of a semilogarithmic relationship between RF and GRK2 activity. Using quantitative real-time RT-PCR, both GRK2 and GRK5 mRNA were not decreased at 24-hrs in EBZ (n = 6 dogs) relative to RS control, indicating the decrease of GRK2 in the EBZ is likely due to post-transcriptional degradation following CAL. Pretreatment of 6 dogs with the selective proteasome inhibitor bortezomib provided 100% (EBZ) and 50% (infarct) protection against loss of GRK2 at 24-hrs. There was an absence of rapid (>300 bpm) and very rapid (>360 bpm) ventricular triplets that are highly predictive of SCD during EKG monitoring in the bortezomib pretreated animals in contrast to non-pretreated infarcted animals. We have demonstrated that the dramatic decrease in GRK2 in cardiac ischemic tissue can be largely blocked by prior proteasome blockade, and this is associated with significant cardio-protection against malignant ventricular tachyarrhythmias.