NEUREGULINS PROMOTE SURVIVAL AND GROWTH OF CARDIAC MYOCYTES - PERSISTENCE OF ERBB2 AND ERBB4 EXPRESSION IN NEONATAL AND ADULT VENTRICULAR MYOCYTES

Neuregulins (i.e. neuregulin-1 (NRG1), also called neu differentiation factor, heregulin, glial growth factor, and acetylcholine receptor-in ducing activity) are known to induce growth and differentiation of epi thelial, glial, neuronal, and skeletal muscle cells. Unexpectedly, mic e with loss of function mutations of NRG1 or of either of two of their cognate receptors, ErbB2 and ErbB4, die during midembryogenesis due t o the aborted development of myocardial trabeculae in ventricular musc le. To examine the role of NRG and their receptors in developing and p ostnatal myocardium, we studied the ability of a soluble NRG1 (recombi nant human glial growth factor 2) to promote proliferation, survival, and growth of isolated neonatal and adult rat cardiac myocytes. Both E rbB2 and ErbB4 receptors were found to be expressed by neonatal and ad ult ventricular myocytes and activated by rhGGF2. rhGGF2 (30 ng/ml) pr ovoked an approximate 2-fold increase in embryonic cardiac myocyte pro liferation, rhGGF2 also promoted survival and inhibited apoptosis of s ubconfluent, serum-deprived myocyte primary cultures and also induced hypertrophic growth in both neonatal and adult ventricular myocytes, w hich was accompanied by enhanced expression of prepro-atrial natriuret ic factor and skeletal cu-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-l, 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 cont inuing role for neuregulins in the myocardial adaption to physiologic stress or injury.