Development of the cardiac beta-adrenergic system in BAX and NGF knockout mice

A primary aim of this dissertation was to partition the role of NGF in neuron survival from differentiation. Neuron counts in the stellate ganglion and cardiac norepinephrine concentrations ([NE]) were measured at P0, P21, and P60. BAX+/- and BAX-/-NGF+/+ mice had elevated neuron counts (p < 0.01). Adult cardiac [NE] was elevated in BAX-/-NGF+/+ mice (p < 0.01), but 40% lower in BAX-/-NGF+/- mice compared to BAX-/-NGF+/+ mice. Therefore, NGF is the primary factor determining cardiac sympathetic innervation density; and BAX deletion enabled normal cardiac sympathetic innervation with limited NGF levels.; Another aim of this dissertation was to determine whether BAX deletion or BAX and NGF deletion altered the beta-adrenergic receptor (betaAR) system. betaAR density and cAMP levels were measured. BAX-/-NGF+/+ (p < 0.05) and BAX-/-NGF+/- (p < 0.001) mice had attenuated betaAR density at all ages. BAX deletion increased cAMP levels whereas concomitant NGF deletion decreased cAMP levels. Thus, deletion of BAX and NGF has a counterbalancing effect on betaAR signaling.; This dissertation also tested the ability of the cardiac betaAR system to compensate to denervation and beta-adrenergic receptor blockade. This question was addressed by: (1) chemical denervation with 6-OHDA and (2) beta blocker treatment with metoprolol. Chemical sympathectomy caused upregulation of betaARs in BAX-/-NGF+/+ and BAX-/-NGF+/- mice at all three ages (p < 0.05), and increased cAMP levels in BAX-/-NGF+/+ mice at P21 and P60, whereas BAX-/-NGF+/- mice had decreased cAMP levels at P21 and P60. This suggests NGF is important in betaAR signaling. Metoprolol treatment during development decreased innervation (p < 0.01) and betaAR density (p < 0.001) in wild-type and null mutant mice. Therefore, BAX deletion enabled the betaAR system to compensate from denervation but not metoprolol administration.; Together, these studies highlight the importance of NGF in determining cardiac sympathetic innervation and modulating betaAR signaling. These studies demonstrate that targeting the apoptosis pathway can be a potential therapy for disorders of the cardiac sympathetic nervous system.