Functional characterization of the human atrial essential myosin light chain (hALC-1) in a transgenic rat model.
Most patients with hypertrophic cardiomyopathy and congenital heart diseases express the atrial essential myosin light chains (ALC-1) in their ventricles, partially replacing the ventricular essential light chains (VLC-1). This VLC-1/ALC-1 isoform shift is correlated with an increase in cross-bridge cycling kinetics as measured using skinned fibers from the hypertrophied ventricles of human hearts. To study the functional importance of hALC-1 in the intact perfused heart, we generated a transgenic rat model (TGR) overexpressing hALC-1 in the heart. Twelve-week-old TGR rats expressed 17 +/- 4 microg hALC-1 per mg of whole SDS-soluble protein. Their perfused heart contractility parameters were evaluated using the Langendorff preparation. Expression of hALC-1 was accompanied by statistically significant improvements (P<0.001) in the contractile parameters of the hearts of the TGR compared to the age matched control (WKY) animals, represented by increases from 20.8 +/- 2.3 to 45.1 +/- 3.6 mmHg/g heart weight in the developed left ventricular pressure, 1,035.7 +/- 89.8 to 2,181 +/- 135.4 mmHg/s in the contraction rate, and 713 +/- 60.2 to 1,364 +/- 137.4 mmHg/s in the relaxation rate in the WKY and the TGR groups respectively. Characterizing the functional effects of hALC-1 at the whole organ level represents a step towards gene therapy of heart failure.
Abdelaziz
Ahmed Ihab
AI
Max-Delbrück-Center for Molecular Medicine (MDC), Molecular Muscle Physiology, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. a.abdelaziz@mdc-berlin.de
Segaric
Jadranka
J
Bartsch
Holger
H
Petzhold
Daria
D
Schlegel
Wolfgang-Peter
WP
Kott
Monika
M
Seefeldt
Ingo
I
Klose
Joachim
J
Bader
Michael
M
Haase
Hannelore
H
Morano
Ingo
I
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D005455:Fluorescent Antibody Technique; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D018994:Myosin Light Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D051381:Rats; D011921:Rats, Inbred WKY; D019076:Transgenes / Q000235:genetics; D017725:Ventricular Pressure
D018994:Myosin Light Chains; D020543:Proteome; C491915:hALC-1 protein, human