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PRECLINICAL STUDY: PRECLINICAL STUDIES

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

Xifu Liu, PhD^_*, Xinhua Gu, MD^_*, Zhaoming Li, PhD^_*, Xinyan Li, MD, PhD^_*, Hui Li, MD^_*, Jianjie Chang, MD^_*, Ping Chen, MD^_*, Jing Jin, BSc^_*, Bing Xi, MSc^_*, Denghong Chen, BSc^_*, Donna Lai, PhD, Robert M. Graham, FAA, MD and Mingdong Zhou, PhD^_*,_*

^_* Zensun Sci & Tech Ltd., Shanghai, China
Victor Chang Cardiac Research Institute and the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia

Manuscript received November 14, 2005; revised manuscript received April 27, 2006, accepted May 30, 2006.

^_* Reprint requests and correspondence: Dr. Mingdong Zhou, Zensun Science and Technology Ltd., 328 Bibo Road, Zhangjiang Science Park, Pudong, Shanghai 201203, P.R. China. (Email: mdzhou{at}zensun.com).

OBJECTIVES: We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta_2a 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.

Abbreviations and Acronyms   cTnI = cardiac troponin I   CV-B3 = Coxsackie virus B3   EF = ejection fraction   ERK = extracellular signal-regulated kinase   FS = fraction of shortening   LAD = left anterior descending coronary artery   LV = left ventricle/ventricular   LVEDD = left ventricular end-diastolic diameter   LVEDP = left ventricular pressure development at end-diastole   LVESD = left ventricular end-systolic diameter   LVESP = left ventricular pressure development at end-systole   MEK = mitogen-activated protein /ERK   NRG = neuregulin   rhNRG-1 = recombinant human neuregulin-1   TCID50 = 50% tissue culture infectious dose

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