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Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats.

Haase, Hannelore and Dobbernack, Gisela and Tünnemann, Gisela and Karczewski, Peter and Cardoso, M Cristina and Petzhold, Daria and Schlegel, Wolfgang-Peter and Lutter, Steffen and Pierschalek, Petra and Behlke, Joachim and Morano, Ingo (2006):
Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats.
20, In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, (7), pp. 865-73, ISSN 1530-6860, [Online-Edition: http://www.cardoso-lab.org/publications/Haase_2006.pdf],
[Article]

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.

Item Type: Article
Erschienen: 2006
Creators: Haase, Hannelore and Dobbernack, Gisela and Tünnemann, Gisela and Karczewski, Peter and Cardoso, M Cristina and Petzhold, Daria and Schlegel, Wolfgang-Peter and Lutter, Steffen and Pierschalek, Petra and Behlke, Joachim and Morano, Ingo
Title: Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats.
Language: German
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.

Journal or Publication Title: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume: 20
Number: 7
Divisions: 10 Department of Biology > Cell Biology and Epigenetics
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10 Department of Biology
Date Deposited: 06 Mar 2010 08:20
Official URL: http://www.cardoso-lab.org/publications/Haase_2006.pdf
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