Published online May 23, 2015. doi: 10.5494/wjh.v5.i2.63
Peer-review started: September 29, 2014
First decision: January 20, 2015
Revised: March 10, 2015
Accepted: April 16, 2015
Article in press: April 18, 2015
Published online: May 23, 2015
Heart failure is one of the leading causes of death today. It is a complex clinical syndrome in which the heart has a reduced contraction ability and decreased viable myocytes. Novel approaches to the clinical management of heart failure have been achieved through an understanding of the molecular pathways necessary for normal heart development. Neuregulin-1 (NRG-1) has emerged as a potential therapeutic target based on the fact that mice null for NRG-1 or receptors mediating its activity, ErbB2 and ErbB4, are embryonic lethal and exhibit severe cardiac defects. Preclinical studies performed with animal models of heart failure demonstrate that treatment with NRG-1 significantly improves heart function and survival. Clinical data further support NRG-1 as a promising drug candidate for the treatment of cardiac dysfunction in patients. Recent studies have revealed the mechanism underlying the therapeutic effects of NRG-1/ErbB signaling in the treatment of heart failure. Through activation of upstream signaling molecules such as phosphoinositide 3-kinase, mitogen-activated protein kinase, and focal adhesion kinase, NRG-1/ErbB pathway activation results in increased cMLCK expression and enhanced intracellular calcium cycling. The former is a regulator of the contractile machinery, and the latter triggers cell contraction and relaxation. In addition, NRG-1/ErbB signaling also influences energy metabolism and induces epigenetic modification in cardiac myocytes in a way that more closely resembles healthy heart. These observations reveal potentially new treatment options for heart failure.
Core tip: Neuregulin (NRG)-1/ErbB signaling plays a critical role in the development of the heart and the maintenance of cardiac function. In both pre-clinical and clinical studies, NRG-1 has demonstrated efficacy as a therapeutic agent for the treatment of heart failure. In model animals and clinical trials, short-term treatment with recombinant NRG-1 protein results in a long-term beneficial effect. Here, the mechanisms underlying the therapeutic effects of NRG-1 during heart failure are reviewed. The results indicate that NRG-1 induces a cardiac reverse remodeling process through the initiation of changes in both cell metabolism and epigenetic modification.