Document Detail

Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart.
MedLine Citation:
PMID:  18615773     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV). METHODS: AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated. RESULTS: AM mRNA increased by 20.9-fold (p < 0.001) in healthy rat heart and improved fractional shortening by 14% (p < 0.05) and ejection fraction by 8% (p < 0.05). In isolated perfused hearts, an increase (p < 0.05) in the first derivative of isovolumic LV pressure rise (dP/dt(max)) without alteration in diastolic properties was noted. The overexpression of AM activated protein kinase Cepsilon and Cdelta isoforms in the LV, whereas p38 mitogen-activated protein kinase activity decreased. Angiotensin II-induced LV hypertrophy was significantly attenuated by AM (p < 0.01) without compromising cardiac contractility. By contrast, AM enhanced LV dilatation (p < 0.01) and anterior wall thinning (p < 0.001) and augmented the deterioration of LV function (p < 0.05) post-infarction. CONCLUSIONS: The results obtained in the present study show that AM overexpression improves LV systolic function without altering cardiac diastolic properties in the normal heart. Moreover, AM is a potent context-dependent modulator of LV remodeling because it promotes an adaptive response in pressure overload-induced LV hypertrophy and triggers a maladaptive process in post-infarction remodeling.
Hanna Leskinen; Tanja Rauma-Pinola; István Szokodi; Risto Kerkelä; Sampsa Pikkarainen; Paavo Uusimaa; Timo Hautala; Olli Vuolteenaho; Heikki Ruskoaho
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The journal of gene medicine     Volume:  10     ISSN:  1521-2254     ISO Abbreviation:  J Gene Med     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-07-28     Completed Date:  2008-10-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815764     Medline TA:  J Gene Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  867-77     Citation Subset:  IM    
Copyright Information:
(c) 2008 John Wiley & Sons, Ltd.
Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocentre Oulu, University of Oulu, Oulu, Finland.
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MeSH Terms
Adenoviridae / drug effects
Adrenomedullin / metabolism*,  pharmacology
Gene Transfer Techniques*
Heart / drug effects,  physiology,  physiopathology*
Heart Ventricles / drug effects
Hypertrophy, Left Ventricular / metabolism,  physiopathology
Myocardial Infarction / physiopathology
Myocardium / metabolism*
RNA, Messenger / metabolism
Rats, Sprague-Dawley
Systole / drug effects
Ventricular Function, Left / drug effects
Reg. No./Substance:
0/RNA, Messenger; 148498-78-6/Adrenomedullin

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