Sufentanil Alleviates Sepsis-Induced Myocardial Injury and Stress Response in Rats through the ERK/GSK-3 β Signaling Axis

Abstract

Objective: To explore the effect and possible mechanism of sufentanil on sepsis-induced myocardial injury and stress response in rats.

Methods: The cecal ligation and puncture (CLP) method was utilized to establish the sepsis model of rats to explore the effect of sufentanil pretreatment with different concentrations on myocardial injury and oxidative stress in CLP rats. Echocardiogram was applied for detecting cardiac hemodynamic parameters in rats; hematoxylin and eosin (HE) staining as well as TUNEL staining was done for observing pathological changes of myocardial tissue and cardiomyocyte apoptosis in rats, respectively; biochemical testing and enzyme-linked immunosorbent assay (ELISA) were done for determining myocardial injury marker level in serum, oxidative stress substances in myocardial tissue, and neuroendocrine hormone level in serum of rats, respectively; finally, Western blot was performed for checking the expression level of ERK/GSK-3β signaling pathway-related proteins in myocardial tissue of rats.

Results: A model of rat with sepsis-induced myocardial injury was constructed with the CLP method. Specifically, this rat model was characterized by obvious cardiac function and tissue damage, cardiomyocyte apoptosis, and oxidative stress response. Sufentanil pretreatment significantly improved cardiac function injury, alleviated pathological injury and oxidative stress response in myocardial tissue, and inhibited cardiomyocyte apoptosis. Specifically, after sufentanil pretreatment, left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were downregulated, and left ventricular ejection fraction (LVEF) was upregulated; the level of B-type natriuretic peptide (BNP) of serum, creatine kinase isoenzyme (CK-MB), and troponin (cTnl) decreased; besides, malondialdehyde (MDA) level was declined, while activities of superoxide dismutase (SOD) and catalase (CAT) were increased. What is more, further mechanism exploration also revealed that sufentanil could reverse the activity of the sepsis-induced ERK/GSK-3β signaling pathway.

Conclusion: Sufentanil has an obvious protective effect on myocardial injury and stress response in CLP rats, and this protective effect may be related to the activation of the ERK/GSK-3β signaling pathway.

Figure 1

Sufentanil can effectively improve cardiac function and relieve myocardial injury in CLP rats. (a)–(c) Echocardiographic assessment of cardiac function-related parameters in each group of rats, including left ventricular end-diastolic dimension (LVEDD (a)), left ventricular end-systolic dimension (LVESD (b)), and left ventricular ejection fraction (LVEF (c)). (d)–(f) Biochemical testing applied to determine the level of myocardial cell injury-indicators BNP (d), CK-MB (e), and cTnl (f) in serum of rats in each group. ^∗∗P < 0.01 vs. the Sham group, ^#P < 0.05 and ^##P < 0.01 vs. the CLP group.

Figure 2

Sufentanil ameliorates cardiac tissue injury and inhibits myocardial apoptosis in CLP rats. (a) HE staining performed to observe the pathological injury of myocardial tissue in each group; (b) the level of apoptosis in the myocardial tissue of rats in each group assessed by TUNEL staining.

Figure 3

Sufentanil suppresses oxidative stress in myocardial tissue of CLP rats. (a)–(c) Biochemical testing for the content of MDA (a) and the activities of SOD (b) and CAT (c) in myocardial tissue of rats in each group. ^∗∗P < 0.01 vs. the Sham group, ^#P < 0.05 and ^##P < 0.01 vs. the CLP group.

Figure 4

Sufentanil decreases the level of ACTH and CORT in plasma of CLP rats. (a)-(b) The level of ACTH (a) and CORT (b) in plasma of CLP rats checked by ELISA. ^∗∗P < 0.01 vs. the Sham group, ^#P < 0.05 and ^##P < 0.01 vs. the CLP group.

Figure 5

Sufentanil regulates the ERK/GSK-3β signaling pathway in CLP rats. (a) Western blot for detecting the level of ERK/GSK-3β signaling pathway-related proteins (p-ERK, ERK, p-GSK-3β, and GSK-3β) in myocardial tissues of rats in each group; (b) image J software utilized to analyze the ratios of p-ERK/ERK and p-GSK-3β/GSK-3β in myocardial tissues of rats in each group, ^∗∗P < 0.01 vs. the Sham group, ^#P < 0.01 vs. the CLP group.