Progress in neuregulin/Erb B signaling and chronic heart failure

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,Erb B2 and Erb B4,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/Erb B 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/Erb B pathway activation results in increased c MLCK 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/Erb B 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.