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Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart.

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.

SUBMITTER: Logan SM

PROVIDER: S-EPMC8065082 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Commonly used anesthetics induce widespread neuronal degeneration in the developing mammalian brain via the oxidative-stress-associated mitochondrial apoptosis pathway. Dysregulation of cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, can result in reactive oxygen species (ROS) formation. Isoflurane has previously been shown to activate this enzyme. Carbon monoxide (CO), as a modulator of CcOX, is of interest because infants and children are routinely exposed to CO during low-flow anesthesia. We have recently demonstrated that low concentrations of CO limit and prevent isoflurane-induced neurotoxicity in the forebrains of newborn mice in a dose-dependent manner. However, the effect of CO on CcOX in the context of anesthetic-induced oxidative stress is unknown. Seven-day-old male CD-1 mice underwent 1h exposure to 0 (air), 5, or 100ppm CO in air with or without isoflurane. Exposure to isoflurane or CO independently increased CcOX kinetic activity and increased ROS within forebrain mitochondria. However, exposure to CO combined with isoflurane paradoxically limited CcOX activation and oxidative stress. There were no changes seen in steady-state levels of CcOX I protein, indicating post-translational modification of CcOX as an etiology for changes in enzyme activity. CO exposure led to differential effects on CcOX subunit I tyrosine phosphorylation depending on concentration, while combined exposure to isoflurane with CO markedly increased the enzyme phosphorylation state. Phosphorylation of tyrosine 304 of CcOX subunit I has been shown to result in strong enzyme inhibition, and the relative reduction in CcOX kinetics following exposure to CO combined with isoflurane may have been due, in part, to such phosphorylation. Taken together, the data suggest that CO modulates CcOX in the developing brain during isoflurane exposure, thereby limiting oxidative stress. These CO-mediated effects could have implications for the development of low-flow anesthesia in infants and children to prevent anesthesia-induced oxidative stress.

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Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart.

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