ABSTRACT
Purpose:
It has been explored that sevoflurane (Sevo) is cardioprotective in myocardial ischemia/reperfusion injury (MI/RI) and mediates microRNA (miRNA) expression that control various physiological systems. Enlightened by that, the work was programmed to decode the mechanism of Sevo and miR-99a with the participation of bromodomain-containing protein 4 (BRD4).
Methods:
MI/RImodel was established on mice. MI/RI modeled mice were exposed to Sevo or injected with miR-99a or BRD4-related vectors to identify their functions in cardiac function, pathological injury, cardiomyocyte apoptosis, inflammation, and oxidative stress in MI/RI mice. MiR-99a and BRD4 expression in myocardial tissues were tested, and their relation was further validated.
Results:
MiR-99a was down-regulated, and BRD4 was up-regulated in MI/RI mice. Sevo up-regulated miR-99a to inhibit BRD4 expression in myocardial tissues of MI/RI mice. Sevo improved cardiac function, relieved myocardial injury, repressed cardiomyocyte apoptosis, and alleviated inflammation and oxidative stress in mice with MI/RI. MiR-99a restoration further enhanced the positive effects of Sevo on mice with MI/RI. Overexpression of BRD4 reversed up-regulation of miR-99a-induced attenuation of MI/RI in mice.
Conclusions:
The work delineated that Sevo up-regulates miR-99a to attenuate MI/RI by inhibiting BRD4.
Key words
Myocardial Ischemia; Reperfusion Injury; Sevoflurane; Bromodomain Containing Proteins; Myocytes; Cardiac
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I/RI: ischemia/reperfusion injury; MI/RI: myocardial ischemia/reperfusion injury; Sevo: sevoflurane; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; CK-MB: creatine kinase-myocardial bound; Mb: myoglobin; cTnI: cardiac troponin I; IL: interleukin; TNF-α: tumor necrosis factor-α; SOD: superoxide dismutase; GSH: glutathione; GSH-Px: glutathione peroxidase; *P < 0.05 compared with the sham group; #P < 0.05 compared with the I/R group; @measurement data were expressed as mean ± standard deviation. One-way analysis of variance was utilized for discrepancy among groups, followed by Tukey’s multiple comparisons test.
I/RI: ischemia/reperfusion injury; MI/RI: myocardial ischemia/reperfusion injury; Sevo: sevoflurane; HE: hematoxylin and eosin; TUNEL: transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; *P < 0.05 compared with the sham group; #P < 0.05 compared with the I/R group; @Measurement data were expressed as mean ± standard deviation. One-way analysis of variance was utilized for discrepancy among groups, followed by Tukey’s multiple comparisons test.
I/RI: ischemia/reperfusion injury; MI/RI: myocardial ischemia/reperfusion injury; Sevo: sevoflurane; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; CK-MB: creatine kinase-myocardial bound; Mb: myoglobin; cTnI: cardiac troponin I; IL: interleukin; TNF-α: tumor necrosis factor-α; SOD: superoxide dismutase; GSH: glutathione; GSH-Px: glutathione peroxidase; HE: hematoxylin and eosin; TUNEL: transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; *P < 0.05 compared with the Sevo + mimic NC group; #P < 0.05 compared with the sham group; ^P < 0.05 compared with the I/R group; @measurement data were expressed as mean ± standard deviation. Discrepancy between two groups was assessed by independent sample t-test. One-way analysis of variance was utilized for discrepancy among groups, followed by Tukey’s multiple comparisons test.
MI/RI: myocardial ischemia/reperfusion injury; Sevo: sevoflurane; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; CK-MB: creatine kinase-myocardial bound; Mb: myoglobin; cTnI: cardiac troponin I; IL: interleukin; TNF-α: tumor necrosis factor-α; SOD: superoxide dismutase; GSH: glutathione; GSH-Px: glutathione peroxidase; HE: hematoxylin and eosin; TUNEL: transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; *P < 0.05 compared with the Sevo + inhibitor NC group; #measurement data were expressed as mean ± standard deviation. Discrepancy between two groups was assessed by independent sample t-test.
BRD4: bromodomain-containing protein 4; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; #P < 0.05 compared with the Sevo + mimic NC group; &P < 0.05 compared with the Sevo + inhibitor NC group; *P < 0.05 compared with the mimic NC group; @measurement data were expressed as mean ± standard deviation. Discrepancy between two groups was assessed by independent sample t-test. One-way analysis of variance was utilized for discrepancy among groups, followed by Tukey’s multiple comparisons test.
BRD4: bromodomain-containing protein 4; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; CK-MB: creatine kinase-myocardial bound; Mb: myoglobin; cTnI: cardiac troponin I; IL: interleukin; TNF-α: tumor necrosis factor-α; SOD: superoxide dismutase; GSH: glutathione; GSH-Px: glutathione peroxidase; MI/IR: myocardial ischemia/reperfusion injury; HE: hematoxylin and eosin; TUNEL: transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; *P < 0.05 compared with the Sevo + miR-99a mimic + oe-NC group; #measurement data were expressed as mean ± standard deviation. Discrepancy between two groups was assessed by independent sample t-test.