Neuregulins Promote Survival and Growth of Cardiac Myocytes

Abstract

Neuregulins (i.e. neuregulin-1 (NRG1), also called neu differentiation factor, heregulin, glial growth factor, and acetylcholine receptor-inducing activity) are known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. Unexpectedly, mice with loss of function mutations of NRG1 or of either of two of their cognate receptors, ErbB2 and ErbB4, die during midembryogenesis due to the aborted development of myocardial trabeculae in ventricular muscle. To examine the role of NRG and their receptors in developing and postnatal myocardium, we studied the ability of a soluble NRG1 (recombinant human glial growth factor 2) to promote proliferation, survival, and growth of isolated neonatal and adult rat cardiac myocytes. Both ErbB2 and ErbB4 receptors were found to be expressed by neonatal and adult ventricular myocytes and activated by rhGGF2. rhGGF2 (30 ng/ml) provoked an approximate 2-fold increase in embryonic cardiac myocyte proliferation. rhGGF2 also promoted survival and inhibited apoptosis of subconfluent, serum-deprived myocyte primary cultures and also induced hypertrophic growth in both neonatal and adult ventricular myocytes, which was accompanied by enhanced expression of prepro-atrial natriuretic factor and skeletal ␣-actin. Moreover, NRG1 mRNA could be detected in coronary microvascular endothelial cell primary cultures prepared from adult rat ventricular muscle. NRG1 expression in these cells was increased by endothelin-1, another locally acting cardiotropic peptide within the heart. The persistent expression of both a neuregulin and its cognate receptors in the postnatal and adult heart suggests a continuing role for neuregulins in the myocardial adaption to physiologic stress or injury.

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…Consistent with this idea, it is known that FGF1 regulates cardiac remodeling by exerting a protective and proliferative effect after MI [18,19]. On the other hand, neuregulins play crucial roles in the adult cardiovascular system by inducing structural organization of sarcomeres, cell integrity, cell-cell adhesion [20], cell survival [21,22] and angiogenesis [23]. In fact, several studies using animal models of heart failure have demonstrated the therapeutic benefits of neuregulins, which improved cardiac performance, attenuated disease markers, and prolonged animal survival [24,25].…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…Subsequent to the clinical trials showing cardiotoxicity from trastuzumab use, emerging research found that HER2 receptors expressed in the membranes of adult cardiomyocytes have an important role in transmitting growth and survival signals 62. In response to the ligand, neuregulin‐1, ErbB2 forms heterodimers that activate cell hypertrophy and survival pathways through activation of the phosphoinositide 3‐kinase and protein kinase A pathways as well as the mitogen‐activated protein kinase cascade 60, 63. In murine models, deletion of ErbB2 leads to development of spontaneous dilated cardiomyopathy and makes these mice more sensitive to triggers of cardiomyopathy such as pressure overload and anthracyclines 64, 65.…”

Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase

“…PI3-K signaling has recently been implicated as having a central role in the pathway leading from an activated RTK to cellular survival (Yao and Cooper, 1995;Franke et al, 1997). NRG-1, a ligand that can activate ErbB4, promotes survival signaling in various cell types (Pinkas-Kramarski et al, 1994;Dong et al, 1995;Bermingham-McDonough et al, 1996;Canoll et al, 1996;Zhao et al, 1998). Our preliminary data suggest that NRG-1 promotes survival of serumstarved NIH3T3 cells expressing ErbB4 CYT-1 but not of cells expressing ErbB4 CYT-2.…”