April 2010

Document Type


Degree Name



Dept. of Physiology and Pharmacology


Oregon Health & Science University


Each year approximately 1.2 million Americans suffer from a myocardial infarction (MI). The most common complication facing patients that survive myocardial infarction is the development of ventricular arrhythmias and sudden cardiac death. Over the last 30 years remodeling of the sympathetic nervous system has emerged as a major factor contributing to post-MI arrhythmias and sudden cardiac death. In particular, regions of sympathetic hyperinnervation and denervation occur in the viable myocardium beyond the infarcted area, resulting in sympathetic heterogeneity and non-uniform transmission to the heart. While elevated nerve growth factor is implicated in sympathetic hyperinnervation, the mechanisms underlying denervation are unknown. Recent studies show that direct activation of the p75 neurotrophin receptor (p75NTR) by brain derived neurotrophic factor (BDNF) causes axon degeneration of sympathetic neurons in vitro and in vivo. BDNF mRNA is transiently upregulated after MI. Therefore, I hypothesized that sympathetic denervation occurs through p75NTR. In the first part of my thesis, I asked whether p75NTR was required for denervation of the viable myocardium adjacent to the infarct (the peri-infarct region) using mice that lack p75NTR (p75NTR-/-). Experiments described in Chapter 2 showed that sympathetic denervation occurred in the peri-infarct region adjacent to the infarct in congenic wildtype mice but not in the p75NTR-/-mice. I also determined that BDNF protein is elevated in the left ventricle after ischemia-reperfusion implicating it as a possible ligand for p75NTR-mediate sympathetic axon degeneration. In addition I found that sympathetic hyperinnervation was exacerbated in p75NTR-/- mice after ischemia-reperfusion. These results suggest that p75NTR plays multiple roles in the development of sympathetic heterogeneity after MI by mediating denervation and attenuating hyperinnervation. In the process of performing the experiments outlined above, I discovered an altered pattern of sympathetic innervation of the p75NTR-/- left ventricle in the absence of MI (Chapter 3). Sympathetic fibers were confined to the subepicardium of the left ventricle, and the subendocardium was virtually devoid of sympathetic innervation. I determined that this altered pattern of sympathetic innervation was likely due to enhanced repulsion by semaphorin3a in the absence of p75NTR. Finally, I went on to determine that the altered pattern of sympathetic innervation had functional consequences. While cardiac hemodynamics were generally unaffected, p75NTR-/- mice showed a significantly higher incidence of premature ventricular complexes. In summary, the data presented in this thesis identify p75NTR as an important mediator of cardiac sympathetic innervation pattern during development and in sympathetic remodeling after MI.




School of Medicine



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