Abstract 1609: GRK2 Overexpression is Deleterious in Myocardial Ischemia-Reperfusion Injury - Inhibition via βARKct Mediates Cardioprotection
BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) is the archetypal GRK which is upregulated in failing myocardium. The carboxyl-terminus of GRK2 (βARKct) has been shown to have beneficial effects in heart failure by inhibiting GRK2, leading to improved cardiac performance. This study elucidates a deleterious effect of increased GRK2-activity in the model of myocardial ischemia-reperfusion (I/R) injury and possible rescue via βARKct gene delivery and myocardial expression.
METHODS: Non-transgenic littermate controls (NLC) and myocardial-specific GRK2-overexpressing or βARKct-transgenic mice were subjected to I/R. Adenoviral delivery of the βARKct gene in rabbits subjected to I/R was achieved via intracoronary delivery. Infarct size was measured by triphenyltetrazolium chloride staining and myocardial apoptosis was assessed with TUNEL staining and caspase-3 enzymatic assay.
RESULTS: Infarct size was significantly enhanced in GRK2 overexpressing mice (45.0±2.8%) compared to controls (31.3±2.3%) whereas βARKct overexpression led to significant reduction of infarct size to 16.8±1.3% compared to both groups (p<0.05). In rabbits βARKct gene delivery imparted protection against I/R significantly reducing infarct size from 30.0±3.0% (control) to 16.8±2.1% (βARKct). Apoptosis was also significantly reduced in the βARKct group compared to enhanced cell death in the GRK2 group compared to NLC mice. Interestingly, pharmacological blocking of the β2-adrenergic receptor (ICI 118551) in the βARKct overexpressors diminished cardioprotection and infarct size was similar to control values.
CONCLUSION: GRK2 overexpression was deleterious in ischemic myocardium whereas its inhibition via βARKct lead to cardioprotection and reduced apoptosis afforded possibly by improved β2AR protective signaling. Taken together, GRK2 inhibition represents a therapeutic approach to reduce acute ischemic injury in the myocardium.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).