gms | German Medical Science

28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

24. bis 27.11.2004, Hannover

Intramyocardial Human Tissue Kallikrein Gene Transfer Stimulates Therapeutic Angiogenesis and Improves Cardiomyocyte Viability in a Mouse Model of Myocardial Infarction

Intramyokardialer humaner Gewebekallikrein Gentransfer stimuliert die therapeutische therapeutische Angiogenese und verbessert die Lebensfähigkeit von Cardiomyocyten in einem Maus Herzinfarktmodell

Meeting Abstract (Hypertonie 2004)

  • F. Spillmann - Charité Universitätsmedizin Berlin
  • S. van Linthout - Charité Universitätsmedizin Berlin
  • G. Graiani - I.N.B.B., Exper. Medicine and Gene Therapy Section Osilo and Alghero, Parma, I
  • C. Lagrasta - I.N.B.B., Exper. Medicine and Gene Therapy Section Osilo and Alghero, Parma, I
  • C. Tschöpe - Charité Universitätsmedizin Berlin
  • P. Madeddu - I.N.B.B., Exper. Medicine and Gene Therapy Section, Osilo and Alghero, Parma, I

Hypertonie 2004. 28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Hannover, 24.-27.11.2004. Düsseldorf, Köln: German Medical Science; 2005. Doc04hochP6

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/hoch2004/04hoch006.shtml

Veröffentlicht: 10. August 2005

© 2005 Spillmann et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Background: The present study supported the hypothesis that human tissue kallikrein (hTK) gene transfer promotes myocardial neovascularization and cardiomyocyte survival, thus preventing post-ischemic left ventricle (LV) remodelling.

Methods: Myocardial infarction (MI) was performed in male CD-1 mice by permanent ligation of the left descending coronary artery, following gene transfer in the MI border zone with an adenoviral vector carrying the hTK gene (Ad.hTK, 107p.f.u.). Controls received NaCl or Ad.Null. Four days later, endothelial nitric oxide synthase (eNOS), VEGF-A, caspase 3, Bcl-2 and Bax expression were determined by real-time PCR. Phospho-Akt (p-Akt) and total Akt protein levels (tot.-Akt) were quantified by Western-Blot. Expression and localisation of the transgene were evaluated by ELISA and qualitative RT-PCR. At 14 days from MI, heart morphology was studied by formalin fixated sections. Capillary- and arteriole density (c.d. and a.d.) were evaluated on silver stained sections. Apoptosis was further examined on TUNEL-stained isolated cardiomyocytes. LV-function was characterised by intracaviter analyses.

Results: Transgenic mRNA was limited to the LV. Ad.hTK increased eNOS expression (2.1-fold, p<0.05 vs. Ad.Null) and Bcl-2/Bax ratio (p<0.01), while it did not affect VEGF-A expression (p=NS). Moreover, Ad.hTK decreased caspase3 expression (p<0.05). The p-Akt/tot-Akt ratio was 1.3-fold higher in the Ad.hTK group (p<0.05 vs. Ad.Null). Ad.hTK reduced LV and septum thickness (both by 14%) at 14 days. In the MI border zone, Ad.hTK increased c. d. and a.d. 1.2-fold (p<0.05) and 1.7-fold (p<0.05), respectively and reduced by 1.6-fold the number of isolated apoptotic cardiomyocytes (p<0.01). These findings correlated with an improved LV function.

Conclusion: Intramyocardial hTK stimulates reparative neovascularization and inhibits cardiomyocyte apoptosis in the area at risk, which correlates with an improved LV function.