PMID- 17005195
OWN - NLM
STAT- MEDLINE
DCOM- 20070227
LR  - 20220317
IS  - 0022-2828 (Print)
IS  - 0022-2828 (Linking)
VI  - 41
IP  - 5
DP  - 2006 Nov
TI  - Neuregulin-1 beta attenuates doxorubicin-induced alterations of 
      excitation-contraction coupling and reduces oxidative stress in adult rat 
      cardiomyocytes.
PG  - 845-54
AB  - Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with 
      trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased 
      incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) 
      and alterations of calcium homeostasis. Therefore, we hypothesized that 
      neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces 
      Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. 
      Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 
      h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 
      and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence 
      microscopy. At clinically relevant doses Doxo reduced cardiomyocytes 
      contractility, SERCA protein and SR calcium content. NRG, similarly as the 
      antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but 
      protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation 
      of glutathione reductase gene expression. NRG, similarly as NAC, reduced 
      peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the 
      antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the 
      Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced 
      alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of 
      the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated 
      with Doxo might prevent beneficial effects of NRG in the myocardium.
FAU - Timolati, Francesco
AU  - Timolati F
AD  - Swiss Cardiovascular Center, University Hospital, CH-3010 Bern, Switzerland.
FAU - Ott, Daniel
AU  - Ott D
FAU - Pentassuglia, Laura
AU  - Pentassuglia L
FAU - Giraud, Marie-Noelle
AU  - Giraud MN
FAU - Perriard, Jean-Claude
AU  - Perriard JC
FAU - Suter, Thomas M
AU  - Suter TM
FAU - Zuppinger, Christian
AU  - Zuppinger C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060926
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Neuregulin-1)
RN  - 0 (neuregulin beta)
RN  - 80168379AG (Doxorubicin)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Calcium/metabolism
MH  - Doxorubicin/antagonists & inhibitors/*pharmacology
MH  - Hydrogen Peroxide/pharmacology
MH  - Male
MH  - Myocardial Contraction/*drug effects
MH  - Myocytes, Cardiac/*drug effects/physiology
MH  - Neuregulin-1/*pharmacology
MH  - *Oxidative Stress
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, ErbB-2/metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases
MH  - Signal Transduction
MH  - Ventricular Function
EDAT- 2006/09/29 09:00
MHDA- 2007/02/28 09:00
CRDT- 2006/09/29 09:00
PHST- 2006/04/27 00:00 [received]
PHST- 2006/07/11 00:00 [revised]
PHST- 2006/08/04 00:00 [accepted]
PHST- 2006/09/29 09:00 [pubmed]
PHST- 2007/02/28 09:00 [medline]
PHST- 2006/09/29 09:00 [entrez]
AID - S0022-2828(06)00759-0 [pii]
AID - 10.1016/j.yjmcc.2006.08.002 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2006 Nov;41(5):845-54. doi: 10.1016/j.yjmcc.2006.08.002. Epub 
      2006 Sep 26.