PMID- 16675844
OWN - NLM
STAT- MEDLINE
DCOM- 20060601
LR  - 20121115
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 20
IP  - 7
DP  - 2006 May
TI  - Minigenes encoding N-terminal domains of human cardiac myosin light chain-1 
      improve heart function of transgenic rats.
PG  - 865-73
AB  - 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.
FAU - Haase, Hannelore
AU  - Haase H
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - Dobbernack, Gisela
AU  - Dobbernack G
FAU - Tunnemann, Gisela
AU  - Tunnemann G
FAU - Karczewski, Peter
AU  - Karczewski P
FAU - Cardoso, Cristina
AU  - Cardoso C
FAU - Petzhold, Daria
AU  - Petzhold D
FAU - Schlegel, Wolfgang-Peter
AU  - Schlegel WP
FAU - Lutter, Steffen
AU  - Lutter S
FAU - Pierschalek, Petra
AU  - Pierschalek P
FAU - Behlke, Joachim
AU  - Behlke J
FAU - Morano, Ingo
AU  - Morano I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Actins)
RN  - 0 (Myosin Light Chains)
RN  - 0 (myosin light chain I)
SB  - IM
MH  - Actins
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Gene Expression Regulation
MH  - Genetic Therapy
MH  - Heart/*physiology
MH  - Humans
MH  - Male
MH  - Myocardial Contraction/*genetics/*physiology
MH  - Myocytes, Cardiac/metabolism
MH  - Myosin Light Chains/*chemistry/genetics/*metabolism
MH  - Protein Binding
MH  - Rats
MH  - Rats, Inbred WKY
EDAT- 2006/05/06 09:00
MHDA- 2006/06/02 09:00
CRDT- 2006/05/06 09:00
PHST- 2006/05/06 09:00 [pubmed]
PHST- 2006/06/02 09:00 [medline]
PHST- 2006/05/06 09:00 [entrez]
AID - 20/7/865 [pii]
AID - 10.1096/fj.05-5414com [doi]
PST - ppublish
SO  - FASEB J. 2006 May;20(7):865-73. doi: 10.1096/fj.05-5414com.