Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins.
Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin (Dox)-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is, therefore, important to understand how NRG1, via erbB2, protects the heart against Dox cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins [cardiac troponin I (cTnI) and cardiac troponin T (cTnT)] and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT, and cardiac troponin C (cTnC) and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2, phosphoinositide 3-kinase (PI3K), Akt, and mTOR blocked the protective effects of NRG1 on cTnI and cTnT in NRVM. NRG1 significantly reduced Dox-induced caspase activation, which degraded troponins, in NRVM. NRG1 reduced Dox-induced proteasome degradation of cTnI. NRG1 attenuates Dox-induced decrease in cardiac troponins by increasing transcription and translation and by inhibiting caspase activation and proteasome degradation of troponin proteins. NRG1 maintains cardiac troponins by the erbB2-PI3K pathway, which may lessen Dox-induced cardiac dysfunction.
Cardiovascular Research, Caritas St. Elizabeth's Medical Center, 736 Cambridge St. CBR3, Boston, MA 02135, USA.
Yun
Y
Bian
Maoyun
M
Sun
Marcy
M
Silver
Kalon K L
KK
Ho
Mark A
MA
Marchionni
Anthony O
AO
Caggiano
James R
JR
Stone
Ivo
I
Amende
Thomas G
TG
Hampton
James P
JP
Morgan
Xinhua
X
Yan
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers / Q000097:blood; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004317:Doxorubicin; D006023:Glycoproteins / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D007279:Injections, Subcutaneous; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D020890:Neuregulin-1 / Q000008:administration & dosage*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D019210:Troponin I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020107:Troponin T / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D002317:Cardiovascular Agents; D020169:Caspases; D003402:Creatine Kinase; D004317:Doxorubicin; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D058570:TOR Serine-Threonine Kinases; D019210:Troponin I; D020107:Troponin T; C094131:NRG1 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; C483804:Erbb2 protein, rat