Title

Reduction of Sympathetic Activity via Adrenal-targeted GRK2 Gene Deletion Attenuates Heart Failure Progression and Improves Cardiac Function after Myocardial Infarction

Authors

Authors

A. Lymperopoulos; G. Rengo; E. H. Gao; S. N. Ebert; G. W. Dorn;W. J. Koch

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

ALPHA(2)-ADRENOCEPTOR SUBTYPES; CATECHOLAMINE RELEASE; RECEPTOR KINASE; NERVOUS-SYSTEM; POLYMORPHISMS; STIMULATION; PHYSIOLOGY; ABLATION; MICE; Biochemistry & Molecular Biology

Abstract

Chronic heart failure (HF) is characterized by sympathetic over-activity and enhanced circulating catecholamines (CAs), which significantly increase HF morbidity and mortality. We recently reported that adrenal G protein-coupled receptor kinase 2 (GRK2) is up-regulated in chronic HF, leading to enhanced CA release via desensitization/down-regulation of the chromaffin cell alpha(2)-adrenergic receptors that normally inhibit CA secretion. We also showed that adrenal GRK2 inhibition decreases circulating CAs and improves cardiac inotropic reserve and function. Herein, we hypothesized that adrenal-targeted GRK2 gene deletion before the onset of HF might be beneficial by reducing sympathetic activation. To specifically delete GRK2 in the chromaffin cells of the adrenal gland, we crossed PNMTCre mice, expressing Cre recombinase under the chromaffin cell-specific phenylethanolamine N-methyltransferase (PNMT) gene promoter, with floxedGRK2 mice. After confirming a significant (similar to 50%) reduction of adrenal GRK2 mRNA and protein levels, the PNMT-driven GRK2 knockout (KO) offspring underwent myocardial infarction (MI) to induce HF. At 4 weeks post-MI, plasma levels of both norepinephrine and epinephrine were reduced in PNMT-driven GRK2 KO, compared with control mice, suggesting markedly reduced post-MI sympathetic activation. This translated in PNMT-driven GRK2 KO mice into improved cardiac function and dimensions as well as amelioration of abnormal cardiac beta-adrenergic receptor signaling at 4 weeks post-MI. Thus, adrenal-targeted GRK2 gene KO decreases circulating CAs, leading to improved cardiac function and beta-adrenergic reserve in post-MI HF. GRK2 inhibition in the adrenal gland might represent a novel sympatholytic strategy that can aid in blocking HF progression.

Journal Title

Journal of Biological Chemistry

Volume

285

Issue/Number

21

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

16378

Last Page

16386

WOS Identifier

WOS:000277715900074

ISSN

0021-9258

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