Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction.
Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G protein-coupled receptor kinase-2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 h after coronary artery ligation in the dog. We previously demonstrated that the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1 h before the onset of ischemia, and this was associated with significant cardioprotection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine whether a clinical window exists following the onset of ischemia for such a protective effect. The treatment of six dogs with the selective proteasome inhibitor bortezomib 1 h after the surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against the loss of GRK2 at 24 h. There was no significant increase of heat shock protein 70(72) in the EBZ of bortezomib-treated animals compared with control. There was a striking absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that is highly predictive of sudden cardiac deaths (SCDs) during electrocardiogram monitoring of the first 24 h in the bortezomib-treated animals in contrast with nontreated 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-h observation period. These data support the concept that proteasome inhibition within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.
Huang
Shijun
S
Endocrinology Division, University of Oklahoma Health Sciences Center and Oklahoma Veteran Affairs Medical Center, Oklahoma City, Oklahoma, USA.
Patterson
Eugene
E
Yu
Xichun
X
Garrett
Marion W
MW
De Aos
Isabel
I
Kem
David C
DC
D000818:Animals; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002395:Catecholamines / Q000502:physiology; D002918:Chymotrypsin / Q000378:metabolism; D003331:Coronary Vessels / Q000502:physiology; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis; D006352:Heart Ventricles; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use; D013610:Tachycardia / Q000517:prevention & control*; D014357:Trypsin / Q000378:metabolism
D001897:Boronic Acids; D002395:Catecholamines; D050884:HSP72 Heat-Shock Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D054770:G-Protein-Coupled Receptor Kinase 3; D002918:Chymotrypsin; D014357:Trypsin