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

Item Type:Article
Title:Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats
Creators Name:Haase, H. and Dobbernack, G. and Tünnemann, G. and Karczewski, P. and Cardoso, C. and Petzhold, D. and Schlegel, W.P. and Lutter, S. and Pierschalek, P. and Behlke, J. and Morano, I.
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.
Keywords:Myosin Light Chain, Actin, Heart, Contractility, Animals, Rats
Source:FASEB Journal
ISSN:0892-6638
Publisher:Federation of American Societies for Experimental Biology (U.S.A.)
Volume:20
Number:7
Page Range:865-873
Date:May 2006
Official Publication:https://doi.org/10.1096/fj.05-5414com
PubMed:View item in PubMed

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