Abstract 318: Adrenal G-Protein Coupled Receptor Kinase (GRK) 2 Activity is a Potential novel Bio-Marker of Sympathetic Outflow in Chronic Heart Failure
Chronic heart failure (HF) is characterized by heightened sympathetic nervous system (SNS) activity reflected by enhanced circulating catecholamines (CA’s). This is thought to lead to adrenergic receptor (AR) desensitization in failing myocardium with enhanced GRK2 activity contributing. We recently found that adrenal GRK2 is up-regulated in mice with chronic HF, leading to enhanced CA release through desensitization/down-regulation of the chromaffin cell α2-ARs that normally exert negative feedback on CA secretion. Herein, we tested the possibility that adrenal GRK2 levels correlate with SNS activity/outflow levels accompanying HF. To do this, we used α2A-AR knock-out (α2AKO) mice, which are known to exhibit elevated basal SNS activity, due to the absence of the presynaptic auto-inhibitory α2A-AR in their central SNS. In α2AKO mice having chronic HF 4 weeks post-myocardial infarction (MI), we found that adrenal GRK2 mRNA and protein levels were significantly increased compared to age-matched HF NLC mice. In addition, adrenal GRK2 was elevated even in sham-operated α2AKO mice, compared to age-matched sham-operated NLC mice. In contrast, adrenal tyrosine hydroxylase (TH) expression was similar between HF α2AKO and NLC mice and between sham α2AKO and NLC mice, although it was significantly increased in HF mice, compared to shams, as expected. Interestingly, α2AKO mice exhibit worse cardiac function than NLC‘s at 4 weeks post-MI, as indicated by decreased fractional shortening (10.5 ± 2.1 % vs. 21.5 ± 1.4 %), increased left ventricular end-diastolic diameter, and decreased +dP/dt response to isoproterenol. Finally, whereas plasma levels of both CA’s were increased in post-MI α2AKO and NLC mice, in sham α2AKO mice norepinephrine was selectively increased compared to sham NLC mice, indicating enhanced basal SNS activity/outflow in α2AKO mice. Taken together, these results suggest that α2AKO mice display increased SNS activity/outflow at rest and worse cardiac function after MI than wild-type mice, and that adrenal GRK2, but not TH, levels seem to correlate well with SNS activity/outflow levels, regardless of HF presence. Consequently, adrenal GRK2 might be a novel bio-indicator of SNS outflow, an important determinant of heart function in chronic HF.