Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart

Hanna Leskinen, Tanja Rauma-Pinola, István Szokodi, Risto Kerkelä, Sampsa Pikkarainen, Paavo Uusimaa, Timo Hautala, Olli Vuolteenaho, Heikki Ruskoaho

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 IV pressure rise (dP/dtmax) 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 < 0.0 1) 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.

Original languageEnglish
Pages (from-to)867-877
Number of pages11
JournalJournal of Gene Medicine
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 1 2008

Keywords

  • Gene transfer
  • Hypertrophy
  • Left ventricular remodeling
  • Myocardial infarction
  • Systolic function

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart'. Together they form a unique fingerprint.

  • Cite this

    Leskinen, H., Rauma-Pinola, T., Szokodi, I., Kerkelä, R., Pikkarainen, S., Uusimaa, P., Hautala, T., Vuolteenaho, O., & Ruskoaho, H. (2008). Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart. Journal of Gene Medicine, 10(8), 867-877. https://doi.org/10.1002/jgm.1219