Abstract 10208: Nardilysin Regulates Circulatory Dynamics Through Modulating Sympathetic Nerve Innervation
We identified nardilysin (Nrd1), a zinc peptidase of the M16 family, as a specific binding partner of HB-EGF, and demonstrated that nardilysin enhances ectodomain shedding of multiple membrane proteins like HB-EGF through activating A Disintegrin And Metalloprotease (ADAM). To explore the physiological roles of nardilysin, we generated nardilysin-deficient mice (Nrd1-/-) and found that nardilysin regulates axonal maturation and myelination in the nervous system partly through modulating neuregulin1 shedding. The role of nardilysin in the cardiovascular system, however, has not been clarified. As Nrd1-/- showed severe hypotension and bradycardia compared with Nrd1+/+ (Nrd1+/+v.s.Nrd1-/-; systolic BP; 110+/-8 v.s.82+/-6mmHg, HR;719+/-44, v.s.579+/-44/min, p<0.001), we assessed sympathetic nervous system (SNS) activity in Nrd1-/- by analysis of heart rate variability and measurement of plasma cathecholamine. In spite of the hypotension and bradycardia, Nrd1-/- showed higher ratio of low- to high-frequency and hypercathecholaminemia, indicating that SNS activity is higher in Nrd1-/-. Next, we examined patterning of sympathetic innervation in Nrd1-/- ventricles by immunostaining of tyrosine hydroxylase. While cardiac sympathetic nerves were located subepicardially in Nrd1+/+ ventricles, Nrd1-/- ventricular myocardium was uniformly innervated from epicardium to endocardium. As Nerve growth factor (NGF) and its receptor p75, are critically involved in the cardiac sympathetic innervation, we examined their expression in Nrd1-/- hearts. In Nrd1-/- ventricles, protein expression level of NGF was significantly reduced whereas p75 shedding was impaired. The role of nardilysin in p75 shedding was also confirmed by co-transfection experiments in vitro, which demonstrated that nardilysin enhances ADAM17-induced p75 shedding. Given that regulated p75 shedding is required for appropriate developmental apoptosis of sympathetic neurons, these in vivo and in vitro results strongly suggested that nardilysin is involved in sympathetic innervation by regulating apoptosis. In summary, nardilysin critically controls circulatory dynamics through modulating cardiac sympathetic innervation probably by regulating p75 shedding.
- © 2011 by American Heart Association, Inc.