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Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context‐dependent in the heart
Author(s) -
Leskinen Hanna,
RaumaPinola Tanja,
Szokodi István,
Kerkelä Risto,
Pikkarainen Sampsa,
Uusimaa Paavo,
Hautala Timo,
Vuolteenaho Olli,
Ruskoaho Heikki
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1219
Subject(s) - medicine , adrenomedullin , pressure overload , ventricle , cardiology , contractility , diastole , cardiac function curve , heart failure , context (archaeology) , myocardial infarction , ejection fraction , angiotensin ii , endocrinology , blood pressure , biology , cardiac hypertrophy , paleontology , receptor
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 Cε and Cδ 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. Copyright © 2008 John Wiley & Sons, Ltd.