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

Hannelore Haase^*, Gisela Dobbernack^*, Gisela Tünnemann^*,, Peter Karczewski^*, Cristina Cardoso^*, Daria Petzhold^*, Wolfgang-Peter Schlegel^*, Steffen Lutter^*, Petra Pierschalek^*, Joachim Behlke^* and Ingo Morano^*,,1

^* Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;

Charité University Medicine, Johannes-Müller-Institute for Physiology, Berlin, Germany; and

Franz-Volhard-Clinics, Berlin, Germany

¹Correspondence: Max-Delbrück-Center for Molecular Medicine, Molecular Muscle Physiology, Robert-Rössle-Str. 10, 13125 Berlin, Germany. E-mail: imorano{at}mdc-berlin.de

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 µM) 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.–Haase, H., Dobbernack, G., Tünnemann, G., Karczewski, P., Cardoso, C., Petzhold, D., Schlegel, W.-P., Lutter, S., Pierschalek, P., Behlke, J. Morano, I. Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 improve heart function of transgenic rats.

Key Words: myosin light chain • actin • heart • contractility • rat

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