Role of activating the nuclear factor kappa B signaling pathway in the development of septic cardiomyopathy in rats with sepsis

Abstract

Background: Despite advances in the treatment of sepsis over time, this condition remains both a serious threat and a cause of death among critical patients.

Objective: This study aimed to explore the role of the nuclear factor kappa B (NF-κB) signaling pathway in the development of septic cardiomyopathy in rats with sepsis.

Method: A total of 32 Sprague Dawley rats were randomized into a sham operation group and three groups with sepsis, which were tested at one of the following time-points: 3, 6, or 12 h. Each group included eight rats. Sepsis models were created via cecal ligation and puncture procedures. All the study rats had the following cardiac parameters and serum levels measured at either 3, 6, or 12 h after the operation (according to their assigned group): heart rate, left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and cardiac troponin I (cTnI). The myocardium of the left ventricle was collected and subjected to hematoxylin and eosin staining to observe the changes in pathological morphology. The expression of toll-like receptor 4 (TLR4) and NF-κB in the myocardium were detected by western blot analysis.

Results: Compared with the sham operation group, the rats in the sepsis subgroups exhibited significantly lower values for all the cardiac parameters measured, including the heart rate (sham operation group = 386.63 ± 18.62 beats per minute [bpm], sepsis 3-h group = 368.38 ± 12.55 bpm, sepsis 6-h group = 341.75 ± 17.05 bpm, sepsis 12-h group = 302.13 ± 21.15 bpm), LVSP (sham operation group = 125.50 ± 11.45 mmHg, sepsis 3-h group = 110.88 ± 7.51 mmHg, sepsis 6-h group = 100.00 ± 15.06 mmHg, sepsis 12-h group = 91.38 ± 14.73 mmHg), +dp/dtmax (sham operation group = 7137.50 ± 276.44 mm Hg/sec, sepsis 3-h group = 5745.00 ± 346.16 mm Hg/sec, sepsis 6-h group = 4360.00 ± 312.04 mm Hg/sec, sepsis 12-h group = 2871.25 ± 443.99 mm Hg/sec), and -dp/dtmax (sham operation group = 6363.75 ± 123.86 mm Hg/sec, sepsis 3-h group = 6018.75 ± 173.49 mm Hg/sec, sepsis 6-h group = 5350.00 ± 337.89 mm Hg/sec, sepsis 12-h group = 4085.00 ± 326.76 mm Hg/sec). They also displayed significantly higher levels of serum cytokines, including TNF-α (sham operation group = 14.72 ± 2.90 pg/mL, sepsis 3-h group = 34.90 ± 4.79 pg/mL, sepsis 6-h group = 24.91 ± 2.57 pg/mL, sepsis 12-h group 22.06 ± 3.11 pg/mL), IL-1β (sham operation group = 42.25 ± 16.91, 3-h group = 112.25 ± 13.77, sepsis 6-h group = 207.90 ± 22.64, sepsis 12-h group = 157.18 ± 23.06), IL-6 (sham operation group = 39.89 ± 5.74, sepsis 3-h group = 78.27 ± 9.31, sepsis 6-h group = 123.75 ± 13.11, sepsis 12-h group = 93.21 ± 8.96), and cTnI (sham operation group = 0.07 ± 0.03 ng/mL, sepsis 3-h group = 0.18 ± 0.06 ng/mL, sepsis 6-h group = 0.67 ± 0.19 ng/mL, sepsis = 12-h group 1.28 ± 0.10 ng/mL). The rats in the sepsis groups exhibited pathological changes in the myocardium, which deteriorated gradually over time. The animals in all the sepsis groups exhibited significantly higher levels of TLR4 and NF-κB protein expression compared with the sham group. The TLR4 protein expressions were 0.376 in the sham operation group, 0.534 in the sepsis 3-h group, 0.551 in the sepsis 6-h group, and 0.719 in the sepsis 12-h group. The NF-κB protein expressions were 0.299 in the sham operation group, 0.488 in the sepsis 3-h group, 0.516 in the sepsis 6-h group, and 0.636 in the sepsis 12-h group.

Conclusion: Sepsis can lead to myocardial injury and cardiac dysfunction. This may be related to the activation of the NF-κB intracellular signal transduction pathway and the release of inflammatory factors as a result of lipopolysaccharides acting on TLR4 during the onset of sepsis.

Keywords: NF-κB signaling pathway; Septic cardiomyopathy; TLR4; interleukin-1β; interleukin-6; tumor necrosis factor-α.