Abstract
BackgroundMiRNA-155 and miRNA-145 have been demonstrated to function as a key regulator in the development of the cardiovascular system. Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion (I/R) injury. This study was designed to investigate if administration of sildenafil will attenuate post-resuscitation myocardial dysfunction by regulating miRNA-155 and miR-145 expressions.MethodsThirty-two male pigs (weighing 30 ± 2 kg) were randomly divided into 4 groups, sildenafil group (n = 8), sildenafil +NG-nitro-l-arginine methyl ester (L-NAME) (20 mg/kg L) group (n = 8), saline (SA group, n = 8); and sham operation group (sham group, n = 8). Eight minutes of untreated VF was followed by defibrillation in anesthetized, closed-chest pigs. Hemodynamic status and blood samples were obtained at 0 min, 0.5, 1, 2, 4 and 6 h after return of spontaneous circulation (ROSC), and the hearts were removed and analyzed under electron microscopy, quantitative real-time polymerase chain reaction and ultra structural analysis were performed to evaluate myocardial injury.ResultsCompared with the sildenafil + L-NAME and saline groups, the sildenafil group had better outcomes in terms of hemodynamic and oxygen metabolism parameters as well as 24-h survival rate, and attenuated myocardial injury; In this study, CA pigs showed evidently increased levels of miR-155-5p and miR-145-5p, while the sildenafil treatment decreased the levels of miR-155-5p and miR-145-5p in CA pigs. In addition, the levels of eNOS was decreased in CA pigs, validating sildenafil attenuating post-resuscitation myocardial dysfunction by regulating miRNA-155 and miR-145 expressions.ConclusionsSildenafil group had better outcomes in terms of hemodynamic and oxygen metabolism parameters as well as 24-h survival rate, inhibited the increases in the miR-155-5p and miR-145-5p levels and attenuated myocardial injury in a porcine model of CA and resuscitation.
Highlights
MiRNA-155 and miRNA-145 have been demonstrated to function as a key regulator in the development of the cardiovascular system
It was reported that the impairment in miRNA functions during normoxia could upregulate the expression of eNOS, implicating miRNAs in the general epigenetic mechanisms involving the posttranscriptional modification of eNOS expression [11]
The cumulative defibrillation energy was significantly lower in sildenafil group than in sildenafil + L-NAME group and SA group (p < 0.05)
Summary
MiRNA-155 and miRNA-145 have been demonstrated to function as a key regulator in the development of the cardiovascular system. Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion (I/R) injury. This study was designed to investigate if administration of sildenafil will attenuate post-resuscitation myocardial dysfunction by regulating miRNA-155 and miR-145 expressions. Global ischemia and reperfusion injury induced by cardiopulmonary resuscitation (CPR) causes so-called post-resuscitation syndrome [2]. Postresuscitation myocardiac dysfunction, an important component of the postcardiac arrest syndrome, is caused by ischemia/reperfusion (I/R) injury and includes primary manifestations such as arrhythmias, myocyte apoptosis, and contractile dysfunction [3]. MiR155 and miR-145 have been demonstrated to function as a key regulator in the development of the cardiovascular system [7, 8]. Preliminary data suggested that miR155 and miR-145 were shown to directly bind to NOS messenger RNA (mRNA) during normoxia [7, 8]
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