Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn

Abstract

The pathological consequences of ischemic heart disease involve signaling through the autonomic nervous system (ANS). While early activation may serve to maintain hemodynamic stability, persistent aberrant sympatho-excitation contributes to the development of lethal arrhythmias and heart failure. We hypothesize that as 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 animals, along with control non-ischemic 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 (IEG) c-fos was up-regulated following acute MI along with fosB, dusp1, dusp2, and egr2. Following chronic MI, there was a persistent yet unique activation of immediate early genes including: fosB, nr4a1, nr4a2, nr4a3, egr3, and tnfaip3. In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and a 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 ANS responses can maintain hemodynamic stability while prolonged maladaptive signals can predispose patients to arrhythmias and heart failure.

Integrated analysis reveals the alterations that LMNA interacts with euchromatin in LMNA mutation-associated dilated cardiomyopathy

“…We further identified the differential binding genes through integrating analysis ChIP-seq and RNA-seq data. For the differential genes associated LMNA alone with euchromatin, we obtained 5 candidate genes (EGR2, NMB, CREBBP, PRF1, and TENM4), of which EGR2 and NMB have been reported to involve in myocardial ischemia and heart failure, respectively [ 30 , 31 ]. Although there are currently no reports about PRF1 and TENM4 involved in heart disease, we noticed that they may be related to LMNA mutation-associated DCM in our research; therefore, they may be the potential biomarkers of DCM, which needs further verification.…”

Characterization of novel lncRNAs in upper thoracic spinal cords of rats with myocardial ischemia‑reperfusion injuries

“…MIRI causes nociceptive chemical and electrical signals that affect dorsal root ganglia and the upper thoracic spinal cord ( 42 ). Previous studies have reported that spinal gene expression is associated with in the development of MIRI ( 9 , 27 ) and have identified the molecular mechanisms during MIRI ( 26 , 27 , 42 ); however, the impact of the spinal process during MIRI requires further investigation.…”

“…Previous studies have reported that the spinal cord is closely associated with the occurrence and development of MIRI ( 9-11 ). Following cardiac ischemia and reperfusion, chemical mediators such as dynorphin and suppresses substance P within the myocardium activate cardiac afferent fibres projecting from the dorsal root ganglion to the upper thoracic dorsal horn of the spinal cord.…”

STAT3 but not STAT5 contributes to the protective effect of electro-acupuncture against myocardial ischemia/reperfusion injury

“…Hic1, a transcriptional repressor that modulates the expression of cell-cycle genes, can affect heart function and be regulated by the IL-6/STAT3 pathway (Wen et al, 2019;Sulston et al, 2017). Gas1, pttg1, Nrtn, and Tnfrsf25 have also been identified as key molecules in the heart tissue by regulating tissue formation, metabolism, apoptosis of cardiomyocytes, and the interaction of cytokine-cytokine receptor in the JAK/STAT pathway Jiang et al, 2019;Saddic et al, 2018).…”