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This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/H1960    most recent 00328.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Yu, X. Articles by Kem, D. C. Search for Related Content PubMed PubMed Citation Articles by Yu, X. Articles by Kem, D. C.

Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction

¹Endocrinology, ²Cardiac Arrhythmia Research Institute, and ⁴Pulmonary and Critical Care, Department of Medicine, and ⁵Department of Pathology, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City; and ³Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

Submitted 4 April 2005 ; accepted in final form 28 June 2005

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

-adrenergic receptor; G protein receptor kinase 2; sudden cardiac death; ventricular arrhythmias; immunofluorescence microscopy

This article has been cited by other articles:

				X. Yu and D. C. Kem Proteasome inhibition during myocardial infarction Cardiovasc Res, October 4, 2009; (2009) cvp309v2. [Abstract] [Full Text] [PDF]

				S. Huang, E. Patterson, X. Yu, M. W. Garrett, I. De Aos, and D. C. Kem Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1298 - H1303. [Abstract] [Full Text] [PDF]