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Nerve Sprouting Contributes to Increased Severity of Ventricular Tachyarrhythmias by Upregulating iGluRs in Rats with Healed Myocardial Necrotic Injury

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Abstract

Sympathetic nerve sprouting in healed myocardial infarction (MI) has been associated with high incidences of lethal arrhythmias, but the underlying mechanisms are largely unknown. This study sought to test that sympathetic hyperinnervation and/or MI remodels the myocardial glutamate signaling and ultimately increases the severity of ventricular tachyarrhythmias. Myocardial necrotic injury (MNI) was created by liquid nitrogen freeze–thawing across an intact diaphragm to mimic MI. Cardiac sympathetic hyperinnervation was induced by chronic subcutaneous injection of 4-methylcatechol, a potent stimulator of nerve growth factor expression. The results showed that sympathetic hyperinnervation with or without MNI upregulated the myocardial expression of ionotropic glutamate receptors (iGluRs), including NMDA receptor (NMDAR) and AMPA receptor (AMPAR), and induced cardiomyocyte apoptosis. Intravenous infusion with either NMDA (12 mg/kg) or AMPA (15 mg/kg) triggered ventricular tachycardia and ventricular fibrillation in rats with healed MNI plus sympathetic hyperinnervation; these arrhythmias were prevented by respective antagonist of NMDAR or AMPAR. We conclude that MNI with sympathetic nerve sprouting upregulates the expression of NMDAR and AMPAR in the myocardium and this impact in turn enhances cardiac responses to stimulations of iGluRs and thus increases the incidence of ventricular tachyarrhythmias.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (31171088, 81000060, and 81071072), the Basic Research Funding (2008PY08 and 2010PY07), and a 973 program (2011CB503902) from the Ministry of Science and Technology of China.

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China

    Jing Lü, Xue Gao, Jingli Gu, Lan Zhou, Shu Guo, Wei Hao & Ji-Min Cao

  2. Laboratory of Cellular Biophysics, Institute of Molecular Medicine, Peking University, Beijing, 100871, China

    Zhuan Zhou

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  1. Jing Lü
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  2. Xue Gao
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  3. Jingli Gu
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  4. Lan Zhou
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  5. Shu Guo
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  6. Wei Hao
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  7. Zhuan Zhou
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  8. Ji-Min Cao
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Correspondence to Ji-Min Cao.

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Cao JM and Gao X are both responsible authors of this work.

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Lü, J., Gao, X., Gu, J. et al. Nerve Sprouting Contributes to Increased Severity of Ventricular Tachyarrhythmias by Upregulating iGluRs in Rats with Healed Myocardial Necrotic Injury. J Mol Neurosci 48, 448–455 (2012). https://doi.org/10.1007/s12031-012-9720-x

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  • DOI: https://doi.org/10.1007/s12031-012-9720-x

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