Neuregulin-1/erbB-Activation Improves Cardiac Function and Survival in Models of Ischemic, Dilated, and Viral Cardiomyopathy

• Published in: Journal of the American College of Cardiology 2006-10, Vol.48 (7), p.1438-1447
• Main Authors: Liu, Xifu, Gu, Xinhua, Li, Zhaoming, Li, Xinyan, Li, Hui, Chang, Jianjie, Chen, Ping, Jin, Jing, Xi, Bing, Chen, Denghong, Lai, Donna, Graham, Robert M., Zhou, Mingdong
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - drug therapy; Cardiomyopathies - virology; Cardiomyopathy; Cardiomyopathy, Dilated - drug therapy; Deoxyribonucleic acid; Disease Models, Animal; DNA; Dogs; Doxorubicin; Echocardiography; Heart; Heart failure; Histopathology; Kinases; Medical sciences; Myocardial Contraction; Myocardial Ischemia - complications; Myocarditis - complications; Myocarditis. Cardiomyopathies; Neuregulin-1 - physiology; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptor, ErbB-2 - physiology; Recombinant Proteins; Rodents; Studies; Survival Analysis; Ventricular Dysfunction, Left - drug therapy
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.05.057

Neuregulin-1/erbB-Activation Improves Cardiac Function and Survival in Models of Ischemic, Dilated, and Viral Cardiomyopathy Xifu Liu, Xinhua Gu, Zhaoming Li, Xinyan Li, Hui Li, Jianjie Chang, Ping Chen, Jing Jin, Bing Xi, Denghong Chen, Donna Lai, Robert M. Graham, Mingdong Zhou The therapeutic potential of an erbB receptor-active 61-residue recombinant neuregulin-1 peptide (rhNRG-1) was evaluated in animal models of heart disease. Whereas hemodynamics and cardiac contractility remained unchanged in normal rats and dogs, rhNRG-1 improved cardiac performance, attenuated pathological changes, and prolonged survival in rodent models of ischemic, viral, and dilated cardiomyopathy, with survival in the ischemic model being additive to angiotensin-converting enzyme inhibition. The rhNRG-1 also improved cardiac function in a canine model of pacing-induced heart failure. Therefore, rhNRG-1 shows promise as a broad-spectrum therapeutic for heart failure due to a variety of common heart diseases. We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta2aisoform) receptor-active peptide (rhNRG-1) in multiple animal models of heart disease. 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. rhNRG-1 was administered IV to animal models of ischemic, dilated, and viral cardiomyopathy, and cardiac function and survival were evaluated. 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. These beneficial effects make rhNRG-1 prom