| 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 |
Related Documents
:
|
8513546 - Noninvasive risk assessment after myocardial infarction. 15170096 - Effects of cellular cardiomyoplasty on ventricular remodeling assessed by doppler echoc... 20413786 - Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced ca... 19382276 - The clinical manifestation of myocardial infarction in elderly patients. 15019536 - Serum homocysteine concentrations, gemfibrozil treatment, and progression of coronary a... 12776766 - Dilated cardiomyopathy after electrical injury: report of two cases. |
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: 2012-06-07 |
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 |
Affiliation:
|
Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328, USA. al806@nova.edu |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 HL087871-06/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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: The L-cysteine/L-cystine shuttle system provides reducing equivalents to the periplasm in Escherichi...
Next Document: Anatomic distribution of deep vein thrombosis in pregnancy.