Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart.
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.
Leskinen
Hanna
H
Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocentre Oulu, University of Oulu, Oulu, Finland.
Rauma-Pinola
Tanja
T
Szokodi
István
I
Kerkelä
Risto
R
Pikkarainen
Sampsa
S
Uusimaa
Paavo
P
Hautala
Timo
T
Vuolteenaho
Olli
O
Ruskoaho
Heikki
H
D000256:Adenoviridae / Q000187:drug effects; D053607:Adrenomedullin / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D018014:Gene Transfer Techniques; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D012333:RNA, Messenger; D053607:Adrenomedullin