Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn.
Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn.
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DOI：
10.1152/ajpheart.00337.2018
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发表时间：
2018-12
期刊：
影响因子：
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通讯作者：
L. Saddic;Kimberly J. Howard-Quijano;Jasmine P Kipke;Y. Kubo;E. Dale;D. Hoover;K. Shivkumar;M. Eghb
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文献类型：
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作者：
L. Saddic;Kimberly J. Howard-Quijano;Jasmine P Kipke;Y. Kubo;E. Dale;D. Hoover;K. Shivkumar;M. Eghb
缺血性心脏病的病理后果涉及通过自主神经系统传递信号。虽然早期激活有助于维持血流动力学稳定，但持续异常的交感神经兴奋会导致致命性心律失常和心力衰竭的发生。我们假设，随着时间的推移，随着心肌对缺血损伤的反应和重塑，胸髓背角也有类似的基因表达变化序列，胸髓背角是从心脏到中枢神经系统的传入纤维的处理中心。在约克夏猪的大型动物模型上诱导急性和慢性心肌缺血(MI)，并取治疗猪和对照非缺血猪的胸背角进行转录组分析。我们确定了32个健康和急性缺血队列之间的差异表达基因，以及46个健康和慢性缺血队列之间的差异表达基因。急性心肌梗死后，典型的即刻早期基因c-fos、FosB、双特异性磷酸酶1和2(DUSP1和Dusp2)以及早期生长反应2(Egr2)均上调。慢性心肌梗死后，即刻早期基因持续而独特地激活，包括FosB、核受体亚家族4 A组成员1-3(nr4a1、nr4a2和nr4a3)、egr3和肿瘤坏死因子-α诱导蛋白3(TNFAIP3)。此外，慢性心肌梗死标志物的差异表达基因在与细胞凋亡、免疫调节和应激反应相关的途径中得到丰富。这些发现支持随着心肌损伤的成熟，背角基因表达变化的动态进展，并可能解释为什么早期适应性自主神经系统反应可以维持血流动力学稳定，而长期的适应不良信号可能使患者易于发生心律失常和心力衰竭。心肌损伤后自主神经系统的新的和值得注意的激活可以提供早期的心血管支持或长期的异常交感兴奋。后者的反应可能导致致命的心律失常和心力衰竭。这项研究提供的证据表明，随着心肌损伤的进展，脊髓背角的基因表达特征正在发生变化。这些变化可以帮助解释为什么适应性神经系统的反应会随着时间的推移而变得不适应。
The pathological consequences of ischemic heart disease involve signaling through the autonomic nervous system. Although early activation may serve to maintain hemodynamic stability, persistent aberrant sympathoexcitation contributes to the development of lethal arrhythmias and heart failure. We hypothesized that as the myocardium reacts and remodels to ischemic injury over time, there is an analogous sequence of gene expression changes in the thoracic spinal cord dorsal horn, the processing center for incoming afferent fibers from the heart to the central nervous system. Acute and chronic myocardial ischemia (MI) was induced in a large animal model of Yorkshire pigs, and the thoracic dorsal horn of treated pigs, along with control nonischemic pigs, was harvested for transcriptome analysis. We identified 32 differentially expressed genes between healthy and acute ischemia cohorts and 46 differentially expressed genes between healthy and chronic ischemia cohorts. The canonical immediate-early gene c-fos was upregulated after acute MI, along with fosB, dual specificity phosphatase 1 and 2 ( dusp1 and dusp2), and early growth response 2 (egr2). After chronic MI, there was a persistent yet unique activation of immediate-early genes, including fosB, nuclear receptor subfamily 4 group A members 1-3 ( nr4a1, nr4a2, and nr4a3), egr3, and TNF-α-induced protein 3 ( tnfaip3). In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and the stress response. These findings support a dynamic progression of gene expression changes in the dorsal horn with maturation of myocardial injury, and they may explain how early adaptive autonomic nervous system responses can maintain hemodynamic stability, whereas prolonged maladaptive signals can predispose patients to arrhythmias and heart failure. NEW & NOTEWORTHY Activation of the autonomic nervous system after myocardial injury can provide early cardiovascular support or prolonged aberrant sympathoexcitation. The later response can lead to lethal arrhythmias and heart failure. This study provides evidence of ongoing changes in the gene expression signature of the spinal cord dorsal horn as myocardial injury progresses over time. These changes could help explain how an adaptive nervous system response can become maladaptive over time.