Abstract 19287: Renal Sympathetic Denervation Preconditions the Myocardium by Inhibiting G Protein-Coupled Receptor Kinase 2 Signaling
Introduction: Renal denervation (RDN) is currently under clinical investigation for the treatment of resistant hypertension. G Protein-Coupled receptor Kinase 2 (GRK2) is classically recognized as a GPCR desensitizing agent, but also elicits non-canonical signaling pathways that promote cell death. We hypothesize that inhibition of the sympathetic nervous system, via RDN, will attenuate myocardial GRK2 signaling and attenuate subsequent myocardial ischemia-reperfusion (MI/R) injury in the setting of hypertension.
Methods: Spontaneously hypertensive rats (SHR) at 20 weeks of age received either bilateral RF-RDN or sham RDN (Biosense Webster Stockert 70 RF generator) of the renal arteries (4 sides x 20 sec at 10 or 0 watts). After 4 wks, SHR were subjected to 30 min. of left coronary artery occlusion + 24 hr. Rep. and myocardial infarct size (INF)/area-at-risk (AAR) was determined. Left ventricle (LV) was collected 4 weeks following RDN for molecular determinations.
Results: RDN produced a significant decrease in LV GRK2 mRNA to 60% of Sham-RDN levels. Although we did not observe a difference in whole cell GRK2 protein levels between groups, phosphorylation at residue Ser670 was significantly down regulated following RF-RDN. Phosphorylation at this residue results in GRK2 mitochondrial translocation and cell death. RF-RDN rats displayed a significant reduction in myocardial INF size per AAR (26.8 vs. 43.9%, p < 0.01) and reduced plasma troponin-I levels (6.8 vs. 10.3 mg/ml) compared to the Sham-RDN group.
Conclusion: RDN protects against myocardial I/R injury in the setting of established hypertension, in part, by inhibiting pro-death GRK2 signaling pathways associated with increased sympathetic nerve activity. Our data suggest that RF-RDN may exert therapeutic benefits that extend beyond blood pressure reduction in the setting of hypertension and acute myocardial infarction.
Author Disclosures: D.J. Polhemus: None. J. Gao: None. R. Trivedi: None. A. Scarborough: None. T. Goodchild: None. F. Smart: None. D. Kapusta: None. D.J. Lefer: None.
- © 2016 by American Heart Association, Inc.