Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy.
OBJECTIVE
We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta2a isoform) receptor-active peptide (rhNRG-1) in multiple animal models of heart disease.


BACKGROUND
Activation of the erbB family of receptor tyrosine kinases by rhNRG-1 could provide a treatment option for heart failure, because neuregulin-stimulated erbB2/erbB4 heterodimerization is not only critical for myocardium formation in early heart development but prevents severe dysfunction of the adult heart and premature death. Disabled erbB-signaling is also implicated in the transition from compensatory hypertrophy to failure, whereas erbB receptor-activation promotes myocardial cell growth and survival and protects against anthracycline-induced cardiomyopathy.


METHODS
rhNRG-1 was administered IV to animal models of ischemic, dilated, and viral cardiomyopathy, and cardiac function and survival were evaluated.


RESULTS
Short-term intravenous administration of rhNRG-1 to normal dogs and rats did not alter hemodynamics or cardiac contractility. In contrast, rhNRG-1 improved cardiac performance, attenuated pathological changes, and prolonged survival in rodent models of ischemic, dilated, and viral cardiomyopathy, with the survival benefits in the ischemic model being additive to those of angiotensin-converting enzyme inhibitor therapy. In addition, despite continued pacing, rhNRG-1 produced global improvements in cardiac function in a canine model of pacing-induced heart failure.


CONCLUSIONS
These beneficial effects make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.
Liu
Xifu
X
Zensun Sci & Tech Ltd., Shanghai, China.
Gu
Xinhua
X
Li
Zhaoming
Z
Li
Xinyan
X
Li
Hui
H
Chang
Jianjie
J
Chen
Ping
P
Jin
Jing
J
Xi
Bing
B
Chen
Denghong
D
Lai
Donna
D
Graham
Robert M
RM
Zhou
Mingdong
M
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000821:virology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004317:Doxorubicin; D004452:Echocardiography; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000150:complications*; D009205:Myocarditis / Q000150:complications; D020890:Neuregulin-1 / Q000502:physiology*; D010446:Peptide Fragments; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D011994:Recombinant Proteins; D016019:Survival Analysis; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*
D004317:Doxorubicin; D020890:Neuregulin-1; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins