Abstract
Anesthetics such as isoflurane are known to cause apoptosis in the developing mammalian brain. However, isoflurane may have protective effects on the heart via relieving ischemia and downregulating genes related to apoptosis. Ischemic preconditioning, e.g. through the use of low levels of carbon monoxide (CO), has promise in preventing ischemia-reperfusion injury and cell death. However, it is still unclear how it either triggers the stress response in neonatal hearts. For this reason, thirty-three microRNAs (miRNAs) known to be differentially expressed following anesthesia and/or ischemic or hypoxic heart damage were investigated in the hearts from neonatal mice exposed to isoflurane or low level of CO, using an air-exposed control group. Only miR-93-5p increased with isoflurane exposure, which may be associated with the suppression of cell death, autophagy, and inflammation. By contrast, twelve miRNAs were differentially expressed in the heart following CO treatment. Many miRNAs previously shown to be responsible for suppressing cell death, autophagy, and myocardial hypertrophy were upregulated (e.g., 125b-3p, 19-3p, and 21a-5p). Finally, some miRNAs (miR-103-3p, miR-1a-3p, miR-199a-1-5p) which have been implicated in regulating energy balance and cardiac contraction were also differentially expressed. Overall, this study demonstrated that CO-mediated miRNA regulation may promote ischemic preconditioning and cardioprotection based on the putative protective roles of the differentially expressed miRNAs explored herein and the consistency of these results with those that have shown positive effects of CO on heart viability following anesthesia and ischemia-reperfusion stress.
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Funding
This work was supported by a discovery grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada (#6793) to Kenneth Storey and the Canada Research Chairs program. Richard J. Levy was funded by an NIH/NINDS grant (#R01NS112706). Samantha Logan holds an NSERC postgraduate scholarship. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Supplemental Table 1
MicroRNAs chosen for targeted RT-qPCR amplification and their expression patterns in the context of anesthesia treatment, hypoxia or ischemia-reperfusion injury (IRI) (XLSX 13 kb)
Supplemental Table 2
RT-qPCR primers used to assess relative miRNA expression levels (XLSX 10 kb)
Supplemental Table 3
Statistical differences in miRNA expression patterns. Differences in expression as determined by a One-way ANOVA with a Tukey post hoc test are marked with unique letters (p<0.05) and shared letters indicate p>0.05. (CSV 3 kb)
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Logan, S.M., Gupta, A., Wang, A. et al. Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart. Cell Stress and Chaperones 26, 541–548 (2021). https://doi.org/10.1007/s12192-021-01199-0
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DOI: https://doi.org/10.1007/s12192-021-01199-0