Document Detail


Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction.
MedLine Citation:
PMID:  20351116     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic heart failure (HF) is characterized by sympathetic overactivity 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 ( approximately 50%) reduction of adrenal GRK2 mRNA and protein levels, the PNMT-driven GRK2 knock-out (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.
Authors:
Anastasios Lymperopoulos; Giuseppe Rengo; Erhe Gao; Steven N Ebert; Gerald W Dorn; Walter J Koch
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-29
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-17     Completed Date:  2010-06-14     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16378-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adrenal Glands / enzymology
Animals
Catecholamines / metabolism
Chromaffin Cells / enzymology*
Chronic Disease
Crosses, Genetic
G-Protein-Coupled Receptor Kinase 2 / genetics,  metabolism*
Gene Deletion*
Heart Failure / enzymology*,  genetics
Humans
Mice
Mice, Transgenic
Myocardial Infarction / enzymology*,  genetics
Receptors, Adrenergic, alpha-2 / genetics,  metabolism
Signal Transduction*
Sympathetic Nervous System / metabolism
Time Factors
Grant Support
ID/Acronym/Agency:
HL075443/HL/NHLBI NIH HHS; HL085503/HL/NHLBI NIH HHS; HL56205/HL/NHLBI NIH HHS; HL61690/HL/NHLBI NIH HHS; P01-HL091799/HL/NHLBI NIH HHS; R01 HL087871/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Catecholamines; 0/Receptors, Adrenergic, alpha-2; EC 2.7.11.15/Adrbk1 protein, mouse; EC 2.7.11.15/G-Protein-Coupled Receptor Kinase 2
Comments/Corrections

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