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Lai D.,Victor Chang Cardiac Research Institute | Lai D.,University of Sydney | Liu X.,Victor Chang Cardiac Research Institute | Liu X.,Zensun Shanghai Science and Technology Ltd. | And 19 more authors.
Circulation Research | Year: 2010

Rationale: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide. Objective: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice. Methods and results: Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants. Conclusions: The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1-ErbB1/4-Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation. © 2010 American Heart Association, Inc.

Jiang Z.,Zensun Shanghai Science and Technology Ltd. | Zhou M.,Zensun Shanghai Science and Technology Ltd.
Current Heart Failure Reports | Year: 2010

Neuregulin-1 (NRG-1), a ligand of receptor tyrosine kinases of the ErbB family, plays a critical role in cardiovascular development and maintenance of adult heart function. Results from cellular, animal, and clinical experiments have shown NRG-1 to be a promising drug candidate for restoring cardiac function after cardiac injury. Various mechanisms have been suggested to be involved in this process, such as improving sarcomeric structure or cell-cell adhesion, promoting proliferation and survival of cardiac myocytes, balancing Ca 2+ homeostasis, modulating inotropic effects, promoting angiogenesis, and preventing atherosclerosis. However, the contribution of these effects to the restoration of cardiac function remains to be estimated, and it may depend on the specific events that led to heart failure. Meanwhile, distinct and crossed signaling pathways downstream of NRG-1 may play a role in these underlying mechanisms, resulting in a complicated network of signaling mediating the function of NRG-1. © 2010 Springer Science+Business Media, LLC.

Zensun Shanghai Science And Technology Ltd. | Date: 2013-03-21

The present invention provides polypeptide variants of neuregulin-1 (NRG-1) that have enhanced or decreased binding affinity to ErbB3 and/or ErbB4. The invention also provides methods of screening and producing polypeptide variants of NRG-1 and methods of using polypeptide variants of NRG-1 for treating diseases.

Gu X.,Sun Yat Sen University | Gu X.,Zensun Shanghai Science and Technology Ltd. | Liu X.,Zensun Shanghai Science and Technology Ltd. | Xu D.,Sun Yat Sen University | And 13 more authors.
Cardiovascular Research | Year: 2010

Aims Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in experimental heart failure models, but the underlying mechanism remains largely unknown. In this study, we evaluated whether rhNRG-1 could improve cardiac function via the cardiac myosin light chain kinase/myosin light chain 2 ventricular (cMLCK/MLC-2v) pathway in rats with myocardial infarction (MI). Methods and resultsRats with MI were intravenously infused with rhNRG-1 (5 g/kg/h) for 7 days through osmotic pumps. The mechanism of action of rhNRG-1 was investigated by assaying the non-infarcted myocardium with gene chips. The cMLCK expression, phosphorylated MLC-2v and cardiac function were significantly up-regulated, as assessed by real-time PCR, Western blot and echocardiography, in those animals treated with rhNRG-1. Moreover, the restoration of rhNRG-1-induced sarcomeric organization in serum-free cultured neonatal rat cardiomyocytes with rhNRG-1 was inhibited by cMLCK RNA interference or ML-7, an inhibitor of MLCKs. Adenovirus containing the rat cMLCK coding region was injected into non-infarcted myocardium, and cardiac function was monitored using echocardiography and a haemodynamic machine. The dP/dt and fractional shortening decreasing significantly after MI, and improved by 15.7 and 32.1, respectively, following local cMLCK application (all P < 0.05).Conclusion Our results suggest that cMLCK is a downstream effector of rhNRG-1 involved in rhNRG-1-induced cardiac function improvement, and that myocardial cMLCK up-regulation can improve cardiac function in rats with MI. © 2010 The Author.

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