Haase, Hannelore ; Dobbernack, Gisela ; Tünnemann, Gisela ; Karczewski, Peter ; Cardoso, M. Cristina ; Petzhold, Daria ; Schlegel, Wolfgang-Peter ; Lutter, Steffen ; Pierschalek, Petra ; Behlke, Joachim ; Morano, Ingo (2006)
Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats.
In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 20 (7)
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
In this study we investigated whether the expression of N-terminal myosin light chain-1 (MLC-1) peptides could improve the intrinsic contractility of the whole heart. We generated transgenic rats (TGR) that overexpressed minigenes encoding the N-terminal 15 amino acids of human atrial MLC-1 (TGR/hALC-1/1-15, lines 7475 and 3966) or human ventricular MLC-1 (TGR/hVLC-1/1-15, lines 6113 and 6114) isoforms in cardiomyocytes. Synthetic N-terminal peptides revealed specific actin binding, with a significantly (P<0.01) lower dissociation constant (K(D)) for the hVLC-1/1-15-actin complex compared with the K(D) value of the hALC-1/1-15-actin complex. Using synthetic hVLC-1/1-15 as a TAT fusion peptide labeled with the fluorochrome TAMRA, we observed specific accumulation of the N-terminal MLC-1 peptide at the sarcomere predominantly within the actin-containing I-band, but also within the actin-myosin overlap zone (A-band) in intact adult cardiomyocytes. For the first time we show that the expression of N-terminal human MLC-1 peptides in TGR (range: 3-6 muM) correlated positively with significant (P<0.001) improvements of the intrinsic contractile state of the isolated perfused heart (Langendorff mode): systolic force generation, as well as the rates of both force generation and relaxation, rose in TGR lines that expressed the transgenic human MLC-1 peptide, but not in a TGR line with undetectable transgene expression levels. The positive inotropic effect of MLC-1 peptides occurred in the absence of a hypertrophic response. Thus, expression of N-terminal domains of MLC-1 represent a valuable tool for the treatment of the failing heart.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2006 |
| Autor(en): | Haase, Hannelore ; Dobbernack, Gisela ; Tünnemann, Gisela ; Karczewski, Peter ; Cardoso, M. Cristina ; Petzhold, Daria ; Schlegel, Wolfgang-Peter ; Lutter, Steffen ; Pierschalek, Petra ; Behlke, Joachim ; Morano, Ingo |
| Art des Eintrags: | Bibliographie |
| Titel: | Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats. |
| Sprache: | Deutsch |
| Publikationsjahr: | 2006 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | The FASEB journal : official publication of the Federation of American Societies for Experimental Biology |
| Jahrgang/Volume einer Zeitschrift: | 20 |
| (Heft-)Nummer: | 7 |
| URL / URN: | http://www.cardoso-lab.org/publications/Haase_2006.pdf |
| Kurzbeschreibung (Abstract): | In this study we investigated whether the expression of N-terminal myosin light chain-1 (MLC-1) peptides could improve the intrinsic contractility of the whole heart. We generated transgenic rats (TGR) that overexpressed minigenes encoding the N-terminal 15 amino acids of human atrial MLC-1 (TGR/hALC-1/1-15, lines 7475 and 3966) or human ventricular MLC-1 (TGR/hVLC-1/1-15, lines 6113 and 6114) isoforms in cardiomyocytes. Synthetic N-terminal peptides revealed specific actin binding, with a significantly (P<0.01) lower dissociation constant (K(D)) for the hVLC-1/1-15-actin complex compared with the K(D) value of the hALC-1/1-15-actin complex. Using synthetic hVLC-1/1-15 as a TAT fusion peptide labeled with the fluorochrome TAMRA, we observed specific accumulation of the N-terminal MLC-1 peptide at the sarcomere predominantly within the actin-containing I-band, but also within the actin-myosin overlap zone (A-band) in intact adult cardiomyocytes. For the first time we show that the expression of N-terminal human MLC-1 peptides in TGR (range: 3-6 muM) correlated positively with significant (P<0.001) improvements of the intrinsic contractile state of the isolated perfused heart (Langendorff mode): systolic force generation, as well as the rates of both force generation and relaxation, rose in TGR lines that expressed the transgenic human MLC-1 peptide, but not in a TGR line with undetectable transgene expression levels. The positive inotropic effect of MLC-1 peptides occurred in the absence of a hypertrophic response. Thus, expression of N-terminal domains of MLC-1 represent a valuable tool for the treatment of the failing heart. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie > Cell Biology and Epigenetics ?? fb10_zoologie ?? 10 Fachbereich Biologie |
| Hinterlegungsdatum: | 06 Mär 2010 08:20 |
| Letzte Änderung: | 05 Mär 2013 09:32 |
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