Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

Abstract

Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of beta-adrenergic receptor (betaAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial alpha2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein-coupled receptor kinase 2 (GRK2). Adrenal gland-specific GRK2 inhibition reversed alpha2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac betaAR signaling and function, and increased sympatholytic efficacy of a alpha2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target.

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

“…55 Importantly, in an initial study directed toward a true gene therapeutic approach, adenoviral-mediated bARKct gene transfer to the adrenal gland of a genetic line of HF mice returned increased catecholamine release back to normal levels, which was accompanied by improved cardiac performance and bAR signaling. 19 Moreover, a rat MI model with adenovirus-mediated expression of bARKct in the adrenal medulla showed decreased plasma catecholamine levels positively influencing hemodynamic parameters and ejection fraction. 19 These are promising data underlining the potential benefits of targeting adrenal GRK2 by gene therapy and with it the sympathetic adrenergic drive involved in HF development and progression.…”

“…19 Moreover, a rat MI model with adenovirus-mediated expression of bARKct in the adrenal medulla showed decreased plasma catecholamine levels positively influencing hemodynamic parameters and ejection fraction. 19 These are promising data underlining the potential benefits of targeting adrenal GRK2 by gene therapy and with it the sympathetic adrenergic drive involved in HF development and progression. However, the studies published to date have only investigated rodent HF models, and clinically relevant large animal models are certainly warranted in order to further evaluate the true potential of adrenal GRK2 inhibition via gene therapy.…”

“…Analogous to dysfunctional bAR signaling in the cardiac myocyte, SNS hyperactivity in HF also causes the dysfunction of a 2c ARs, and we have shown that this is triggered by adrenal GRK2 upregulation in the adrenal medulla. 19 Enhanced GRK2 activity in the adrenal gland was seen in a mouse model of HF and also in post-MI rats, causing the local desensitization of a 2c ARs. 19 As a consequence, the inhibitory effect of a 2c AR on catecholamine release is abrogated, with the net effect being chronically elevated epinephrine and norepinephrine plasma levels contributing to the progression of HF.…”

“…19 Enhanced GRK2 activity in the adrenal gland was seen in a mouse model of HF and also in post-MI rats, causing the local desensitization of a 2c ARs. 19 As a consequence, the inhibitory effect of a 2c AR on catecholamine release is abrogated, with the net effect being chronically elevated epinephrine and norepinephrine plasma levels contributing to the progression of HF. The hypothesis that GRK2 modulates chromaffin catecholamine secretion was further supported by experiments with adenoviral-mediated overexpression of GRK2 in rats as this caused an increase of plasma catecholamine levels.…”

“…10,17 Indeed, it is upregulated in patients with HF and it has also been observed in several animal models. 10,[18][19][20][21] Moreover, enhanced GRK2 expression has been linked to hypertension, 22 cardiac hypertrophy 23 and postmyocardial infarction (MI). 24 In consideration of the fact that GRK2 levels often increase before manifested clinical HF, 25 and normalize again with advanced b-adrenergic signaling and ventricular function, 26,27 GRK2 not only represents a potential biomarker of cardiac function, 28 but is also an attractive therapeutic target for HF treatment.…”