Document Detail


AAV6.βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model.
MedLine Citation:
PMID:  22261894     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: G protein-coupled receptor kinase 2 (GRK2), which is markedly upregulated in failing human myocardium, has been implicated as a contributing factor or consequence of heart failure (HF). Importantly, cardiac-specific GRK2 knockout mice have recently proved the pathological nature of GRK2 in HF. Targeted inhibition of GRK2 is possible using a peptide inhibitor known as the βARKct, which has rescued several disparate small animal HF models. This study was designed to evaluate long-term βARKct expression in a clinically relevant large animal HF model, using stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6).
METHODS AND RESULTS: A porcine model of HF subsequent to left ventricular (LV) myocardial infarction (MI) was used to study the effects of retrograde injection into the anterior interventricular vein of either AAV6.βARKct or AAV6.luciferase as a control 2 weeks after MI. Echocardiography and LV hemodynamics were performed before and 6 weeks after gene transfer. Robust and long-term βARKct expression was found after AAV6-mediated delivery, leading to significant amelioration of LV haemodynamics and contractile function in HF pigs compared with AAV6.luciferase-treated control animals that showed a continued decline in cardiac function. Interestingly, the neurohormonal axis was virtually normalized in AVV6.βARKct-treated HF animals, represented by reductions in plasma norepinephrine levels, whereas AAV6.luciferase-treated pigs showed further increases in plasma catecholamine levels. As a result, LV remodelling and foetal gene expression was reversed by AVV6.βARKct gene therapy.
CONCLUSION: These data--showing sustained amelioration of cardiac function in a post-MI pig HF model--demonstrate the therapeutic potential of βARKct gene therapy for HF.
Authors:
Philip W J Raake; Philipp Schlegel; Jan Ksienzyk; Julia Reinkober; Jens Barthelmes; Stefanie Schinkel; Sven Pleger; Walter Mier; Uwe Haberkorn; Walter J Koch; Hugo A Katus; Patrick Most; Oliver J Müller
Related Documents :
1258794 - Methylprednisolone treatment in acute myocardial infarction. effect on regional and glo...
20843674 - Ectopic thyroid tissue in the periaortic area, cardiac cavity and aortic valve in a bea...
22571834 - Myocardial damage in dogs affected by heartworm disease (dirofilaria immitis): immunohi...
9562004 - Transient ischemia does not limit subsequent ischemic regional dysfunction in humans: a...
8644594 - Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic...
12007684 - Reactive oxygen species contribute to contractile dysfunction following rapid ventricul...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-19
Journal Detail:
Title:  European heart journal     Volume:  34     ISSN:  1522-9645     ISO Abbreviation:  Eur. Heart J.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-15     Completed Date:  2014-01-07     Revised Date:  2014-05-14    
Medline Journal Info:
Nlm Unique ID:  8006263     Medline TA:  Eur Heart J     Country:  England    
Other Details:
Languages:  eng     Pagination:  1437-47     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adenoviridae
Animals
Catecholamines / metabolism
Coronary Vessels
Echocardiography
Gene Transfer Techniques
Genetic Therapy / methods*
Genetic Vectors
Heart Failure / physiopathology,  therapy*
Hemodynamics / physiology
Luciferases / genetics
Myocardial Infarction / physiopathology,  therapy
Peptides / genetics,  metabolism,  therapeutic use*
Random Allocation
Receptors, CCR10 / antagonists & inhibitors*
Recombinant Proteins / genetics,  metabolism,  therapeutic use*
Sus scrofa
Transgenes / genetics
Ventricular Remodeling / physiology
Grant Support
ID/Acronym/Agency:
P01 HL075443/HL/NHLBI NIH HHS; R01 HL56205/HL/NHLBI NIH HHS; R01 HL61690/HL/NHLBI NIH HHS; R01 HL92130/HL/NHLBI NIH HHS; R01 HL92130-02 S1/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Catecholamines; 0/Peptides; 0/Receptors, CCR10; 0/Recombinant Proteins; 0/beta-adrenergic receptor kinase inhibitory peptide; EC 1.13.12.-/Luciferases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysi...
Next Document:  Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases.