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Macrophage depletion suppresses sympathetic hyperinnervation following myocardial infarction

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Abstract

Myocardial infarction induces sympathetic axon sprouting adjacent to the necrotic region, and this has been implicated in the etiology of arrhythmias resulting in sudden cardiac death. Previous studies show that nerve growth factor (NGF) is essential for enhanced post-infarct sympathetic sprouting, but the cell types necessary to supply this neurotrophic protein are unknown. The objective of the present study was to determine whether macrophages, which are known to synthesize NGF, are necessary for post-infarct cardiac sympathetic sprouting. Ovariectomized female rats received left coronary artery ligation or sham operation, followed by intravenous injection of liposomes containing saline vehicle or clodronate, which kills macrophages. Sham-operated myocardium contained some sympathetic axons, few myofibroblasts and T cells and no CD-68-positive macrophages. In rats receiving saline liposomes through 7 days post-ligation, the posterolateral infarct border contained numerous myofibroblasts, macrophages and T cells, and sympathetic innervation was increased twofold. Treatment with clodronate liposomes reduced macrophage numbers by 69%, while myofibroblast area was reduced by 23% and T cell number was unaffected. Clodronate liposome treatment reduced sympathetic axon density to levels comparable to the uninfarcted heart. NGF protein content measured in western blots was reduced to 33% of that present in infarcts where rats received saline-containing liposomes. Tissue morphometry confirmed that NGF immunostaining was dramatically reduced, and this was attributable primarily to reduced macrophage content. These results show that macrophage destruction markedly reduces post-infarction levels of NGF and that the presence of elevated numbers of macrophages is obligatory for development of sympathetic hyperinnervation following myocardial infarction.

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Acknowledgments

Supported by NIH HL079652, RR016475, and P30HD02528. Clodronate was a gift of Roche Diagnostics GmbH, Mannheim, Germany. We thank Dr. Donald Warn of the Kansas Intellectual and Developmental Disabilities Research Center Integrative Imaging Core for his assistance with imaging, Zhaohui Liao, Argenia Doss and Sarah Tague for their assistance with the animal preparations.

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  1. Department of Molecular and Integrative Physiology, Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Mail Stop 3051, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Gwenaelle Wernli, Wohaib Hasan, Aritra Bhattacherjee & Peter G. Smith

  2. Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands

    Nico van Rooijen

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  1. Gwenaelle Wernli
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  2. Wohaib Hasan
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Wernli, G., Hasan, W., Bhattacherjee, A. et al. Macrophage depletion suppresses sympathetic hyperinnervation following myocardial infarction. Basic Res Cardiol 104, 681–693 (2009). https://doi.org/10.1007/s00395-009-0033-3

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