Abstract
BackgroundChronic myocardial infarction (MI) triggers pathological remodeling in the heart and cardiac nervous system. Abnormal function of the autonomic nervous system (ANS), including stellate ganglia (SG) and dorsal root ganglia (DRG) contribute to increased sympathoexcitation, cardiac dysfunction and arrythmogenesis. ANS modulation is a therapeutic target for arrhythmia associated with cardiac injury. However, the molecular mechanism involved in the pathological remodeling in ANS following cardiac injury remains to be established.Methods and resultsIn this study, we performed transcriptome analysis by RNA-sequencing in thoracic SG and (T1-T4) DRG obtained from Yorkshire pigs following either acute (3 to 5 hours) or chronic (8 weeks) myocardial infarction. By differential expression and weighted gene co-expression network analysis (WGCNA), we identified significant transcriptome changes and specific gene modules in the ANS tissues in response to myocardial infarction at either acute or chronic phases. Both differential expressed genes and the member genes of the WGCNA gene module associated with post-infarct condition were significantly enriched for inflammatory signaling and apoptotic cell death. Targeted validation analysis supported a significant induction of inflammatory and apoptotic signal in both SG and DRG following myocardial infarction, along with cellular evidence of apoptosis induction based on TUNEL analysis. Importantly, these molecular changes were observed specifically in the thoracic segments but not in their counterparts obtained from lumbar sections.ConclusionMyocardial injury leads to time-dependent global changes in gene expression in the innervating ANS. Induction of inflammatory gene expression and loss of neuron cell viability in SG and DRG are potential novel mechanisms contributing to abnormal ANS function which can promote cardiac arrhythmia and pathological remodeling in myocardium.
Highlights
Myocardial ischemia induces changes in the neurohumoral control systems, including sympathoexcitation, that contribute to autonomic nervous system (ANS) imbalance and myocardial remodeling[1, 2] [3]
Myocardial injury leads to time-dependent global changes in gene expression in the innervating ANS
stellate ganglia (SG) and dorsal root ganglia (DRG) are potential novel mechanisms contributing to abnormal ANS function which can promote cardiac arrhythmia and pathological remodeling in myocardium
Summary
Myocardial ischemia induces changes in the neurohumoral control systems, including sympathoexcitation, that contribute to autonomic nervous system (ANS) imbalance and myocardial remodeling[1, 2] [3]. The extrinsic cardiac ANS, including spinal cord, dorsal root ganglia and stellate ganglia, mediate connections between the heart and the central nervous system. Neural remodeling has been demonstrated in the intrinsic cardiac ANS and extracardiac intrathoracic sympathetic ganglia, it likewise may be manifested throughout the extracardiac ANS including the spinal cord and dorsal root ganglia[15, 16]. Abnormal function of the autonomic nervous system (ANS), including stellate ganglia (SG) and dorsal root ganglia (DRG) contribute to increased sympathoexcitation, cardiac dysfunction and arrythmogenesis. The molecular mechanism involved in the pathological remodeling in ANS following cardiac injury remains to be established
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