Research ReportSympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats
Introduction
Arrhythmias are frequent complications of myocardial infarction, occurring most often in the first 30 days following the event (Solomon et al., 2005). While increased sympathetic drive and altered ventricular conduction are clearly contributory (Schomig, 1990, Du et al., 1999, Lal et al., 2005), recent evidence suggests that sympathetic axon remodeling in ventricular myocardium may be a major factor. Postmortem analyses of infarcted human myocardium show abnormal increases in numbers of sympathetic axons adjacent to the site of injury (Cao et al., 2000a). Ischemic injury appears to be the cause of the remodeling, as coronary artery ligation induces hyperinnervation in dogs (Lai et al., 2000, Zhou et al., 2004) and rats (Ahonen et al., 1975, Paessens and Borchard, 1980, Holmgren et al., 1981, Vracko et al., 1990, Kaye et al., 2000, Li et al., 2004). Through enhanced norepinephrine-mediated myocardial depolarization, abnormally increased sympathetic nerve density may be proarrhythmogenic and represent a significant factor in post-infarct sudden cardiac death.
The cellular and molecular mechanisms leading to post-infarct sympathetic hyperinnervation remain incompletely understood. However, the neurotrophin nerve growth factor (NGF) is strongly implicated. NGF is a potent growth and survival factor for sympathetic neurons (Korsching and Thoenen, 1985, Glebova and Ginty, 2004). Recent evidence indicates that NGF expression is up-regulated in the region of the infarction (Hiltunen et al., 2001, Zhou et al., 2004), and infusion of NGF into the stellate ganglion results in cardiac hyperinnervation in canine hearts (Cao et al., 2000b). However, the cell types involved in post-infarct cardiac NGF production and the neural selectivity of the response are not well defined. Similarly, while exogenous NGF can cause sympathetic sprouting there is no definitive evidence that endogenous NGF is required for cardiac sympathetic sprouting in the post-infarct heart.
The objective of the present study was to assess whether inflammatory cells, which are present in the infarcted myocardium (Vracko and Thorning, 1991, Desmouliére et al., 1996) and may synthesize NGF in other contexts (Matsuda et al., 1998, Hasan et al., 2000, Aloe, 2004, Kawamoto and Matsuda, 2004), serve as a local source of NGF which in turn initiates sympathetic sprouting. Accordingly, we assessed whether inflammatory cells express NGF and whether expression is temporo-spatially consistent with the observed pattern of hyperinnervation. Additionally, the requirement for NGF release by this tissue in inducing sympathetic sprouting was assessed by antibody neutralization explant culture studies. The present study provides novel evidence that inflammatory myofibroblasts and macrophages play a central role in peri-infarct NGF synthesis, and that inflammatory cell-derived NGF is required for and sufficient to induce selective sprouting of cardiac sympathetic axons.
Section snippets
Axons and inflammatory cells in ventricular myocardium following artery ligation
Coronary artery ligation resulted in development of a ventricular infarct at post ligation days (PLD) 1–28 (Fig. 1).
Cardiac sympathetic hyperinnervation as sequelae of the inflammatory repair process
Myocardial infarction results in rapid remodeling of ventricular sympathetic innervation. Within 4 days of coronary artery ligation, sympathetic innervation in the peri-infarct zone is substantially greater than that of normal myocardium. Sympathetic hyperinnervation occurs selectively in regions containing abundant myofibroblasts and macrophages. This spatial association is consistent with the idea that these cells provide molecular signals attractive to ingrowing sympathetic axons. Further,
Coronary artery ligation
Female Sprague-Dawley rats (60–70 days postnatal, ∼ 225 g, Harlan Breeding Laboratories, Indianapolis, IN) were anesthetized by intraperitoneal injection of 60 mg/kg ketamine, 8 mg/kg xylazine, and 0.4 mg/kg atropine and ovariectomized bilaterally via flank incisions (Zoubina et al., 2001). Ovariectomy eliminates potentially confounding effects of reproductive hormones which can influence both cardiovascular innervation and wound healing (Gillardon et al., 1991, Saleh and Connell, 2000, Ashcroft
Acknowledgments
Supported by NIH HL079652 with core support by RR016475 and HD02528. We thank Dr. Deborah Scheuer for helping with the coronary artery ligations, Dr. Dora Krizsan-Agbas and Ms. Alison Ting for helping with the surgeries and for critical reading of the manuscript, and Dr. Donald Warn of the MRRC Integrative Imaging Core for his assistance with imaging.
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