Ac 2-26 reduced pyroptosis to ameliorate the cerebral injury in rats after cardiopulmonary bypass via the AKT1-eNOS pathway

doi:10.21203/rs.3.rs-2755707/v1

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Ac 2-26 reduced pyroptosis to ameliorate the cerebral injury in rats after cardiopulmonary bypass via the AKT1-eNOS pathway

https://doi.org/10.21203/rs.3.rs-2755707/v1

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Background: Cardiopulmonary bypass (CPB) generally results inbrain injury, which is primarily caused by inflammation. Ac2-26 protects against multiple organ injury via anti-inflammatory activities. The present study evaluated the effect of Ac2-26 on brain injury in CPB rats.

Methods: A total of 40 rats were randomized into sham, CPB, Ac, and Ac/AKT1 groups. The sham group only received anesthesia, intubation and cannulation, and rats in the other groups underwent the standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac and Ac/AKT1 groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1 group were injected with shRNA (AKT1) 3 days before CPB. The neurological function score and brain edema were evaluated 12 hours after CPB, and brain pathological injury and hippocampal apoptosis were assessed. The levels of TNF-α, IL-1β, IL-6, IL-10, S100β and NSE were tested. AKT1, eNOS, and phosphorylated NF-κB in the brain were also detected.

Results: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury and hippocampal apoptosis. Ac2-26 also reduced the proinflammatory factorsS100β and NSE but increased IL-10. Ac2-26 decreased phosphorylated NF-κB, Bax and cleaved caspase-3 but increased Bcl-2. AKT1 shRNA significantly reversed the protective effect of Ac2-26.

Conclusions: Ac2-26 significantly improved neurological function, reduced brain injury, regulated inflammation, and inhibited apoptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1.

Brain injury

Cardiopulmonary bypass

Inflammation

Ac2-26

Cardiopulmonary bypass (CPB) is an essential support for several cardiac surgeries. However, CPB results in severe postoperative cerebral dysfunction[1], which is characterized by stroke[2], cognitive dysfunction[3] and delirium[4]. The incidences of stroke, delirium and cognitive dysfunction are 1.7%-to-5.4%[2], 20%-to-50%[5], and 30%-to-80%[6], respectively. Cerebral dysfunction prolongs the stay in the ICU and hospital, induces physical disability[7], increases medical care costs[8], and increases postoperative mortality[9]. Many studies indicated that local inflammation induced by cerebral ischemia hypoperfusion and systemic inflammatory response syndrome (SIRS) contributed to the postoperative cerebral dysfunction[10, 11]. Although several treatments have been used in clinical work, the incidence of neurological morbidity remain higher and continuously influences the postoperative quality of patients[12].

Ac2-26 is an activated peptide of annexin A1 that mitigates brain injuries by activating formyl peptide receptors[13, 14]. Zhang et al. also suggested that the tripeptide of annexin A1 reduced brain injury after CPB [15]. However, this study did not explore the mechanism of the tripeptide of annexin A1. Our previous studies found that Ac2-26 prevented lung and brain reperfusion injury by enhancing the expression of eNOS [16, 17]. The Akt/GSK3β pathway has also been implicated in the pathology of brain injury after CPB[18]. Considering the important role of AKT1 in the regulation of eNOS, the present study used a rat CPB model to investigate whether the protective effect of Ac2-26 on brain injury after CPB was mediated by enhancing AKT1.

Thirty-two male SD rats (400-450 g) were purchased from Harbin Medical University and randomized into sham, CPB, Ac, and Ac/AKT1 groups. Rats in the sham group received anesthesia, intubation and catheterization, and the other rats underwent standard CPB[19]. Rats in the sham and CPB groups were intravenously injected with saline, and rats in the Ac and Ac/AKT1 groups were injected with Ac2-26 or Ac2-26 combined with shRNA (AKT1). Rats in the Ac/AKT1 group were injected with shRNA preoperatively for 3 days according to our preliminary study.

CPB procedure

The rats were anesthetized with 3% sodium pentobarbital (30 mg/kg). After anesthesia, all of the rats received intubation with a 12-G catheter for mechanical ventilation (Model 683, Harvard Apparatus, Boston, USA). The ventilated parameters were set at 50% oxygen and 50% nitrogen with 2-cm H₂O positive end-expiratory pressure (Vt: 8 ml/kg, respiratory rate: 50 breaths/min, and inspiratory expiratory ratio 1:1). Under local anesthesia with 1% lidocaine, the right artery and vein and the right femoral artery and vein were catheterized. Heparin (500 IU/kg) was injected for heparinization, and the CPB circuit was inserted. The CPB circuit included a venous reservoir (20 ml), roller pump (Cole Parmer Instrument Company, Chicago, USA) and membrane oxygenator (MeicroPort, Dongguan, Guangdong, China). After priming with 0.2 ml heparin, 11 ml of a hydroethyl starch solution and 0.5 ml 7% sodium bicarbonate solution, the flow rate was gradually up-regulated to 100 ml/kg/min for 60 min[20]. Immediately after the initiation of CPB, rats in the CPB group received saline (0.5 ml), and rats in the Ac and Ac/AKT1 groups were injected with Ac2-26 (1 mg/kg diluted into 0.5 ml) [16, 17]. Rats in the Ac/AKT1 group were intravenously injected with shRNA (1 × 10⁵ ifu/L AKT1 expression lentiviral solution at 150 μL/100 g body weight) to knock down AKT1 expression preoperatively for 3 days according to our preliminary study.

During CPB, the mean arterial pressure was maintained over 70 mmHg with adrenalin, and the temperature was maintained at 36 to 38 ℃. After 60 min of CPB, protamine (5 mg/kg)[21] was injected for anti-heparinization, the outflow was withdrawn first. The inflow was stopped when hemodynamic stabilization was achieved. All catheters were withdrawn, and the incisions were saturated after the injection of 2000 U/kg penicillin to prevent infection. All rats were extubated when they recovered spontaneous breathing. After 12 hours of CPB, the neurological function of all rats was tested. All rats were injected with heparin and sacrificed via an overdose of anesthetics[22].

Neurological function score

Neurological function was scored according to the following criteria: prehensile traction, strength and balance beam performance were graded on a 0-9 scale (best score = 0, worst score =9). Evaluations of neurological function were performed according to a previous study[15].

Brain edema

After sacrifice, part of the brain tissue was collected and weighed after removal of the parietal cortex and hippocampus. The brain tissue was dried at 80 °C for 48 hours and weighed again. Brain edema was calculated using the (wet weight – dry weight)/wet weight ratio.

Histological evaluation

Brain hippocampal tissue was collected and fixed in neutral formalin. The tissue was dehydrated with ethanol, cleared with xylene, and embedded in paraffin. The brain tissue was cut into 4-μm sections and stained with HE. After staining, an independent pathologist who did not participate in this study assessed pathological injuries using light microscopy.

Survival and apoptosis assessment

Neuronal survival was analyzed using Nissl staining. The brain tissues were fixed with 4% paraformaldehyde and placed on polylysine-coated slides overnight. After rehydration, the sections were submerged in 1% cresyl violet before staining. The surviving neurons of the hippocampal CA1 region exhibited the standard of characteristics of a visible nucleus and intact cytoplasm. An independent pathologist counted the surviving neurons.

Brain hippocampal apoptosis was estimated using a TUNEL kit (Roche). The 4-μm sections were washed twice with PBS and mixed with biotinylated nucleotides and terminal deoxynucleotidyl transferase at 37 °C for 60 min. After washing with PBS, the sections were blocked with 0.3% hydrogen peroxide and rinsed with 50 μl of TUNEL reaction mixture for 60 min at 37 °C. The section was stained with Mayer’s hematoxylin and dehydrated. Apoptotic cells were identified with brown nuclei under microscopy.

Cytokine measurement in the serum and brain

To observe the effect of Ac2-26 on systemic and local inflammation, we detected TNF-α, IL-1β, IL-6, and IL-10 levels in the serum and brain hippocampus and S100β and NSE in the brain using commercial ELISA kits (Wuhan, China). Peripheral blood was collected at baseline and 12 hours after CPB then centrifuged at 2,000 × g for 10 min at 4 °C. The supernatant was collected at -80 °C for testing. The brain tissue was collected and homogenized in saline (1:9) to prepare brain homogenates. The homogenate was centrifuged at 14,000 × g for 10 min at 4 °C, and the supernatant was collected. All supernatants were tested using ELISA kits according to the manufacturer’s instructions.

Western blotting

Brain hippocampal samples were lysed with RIPA buffer. The protein levels in brain tissue were detected using the Bradford method. After confirmation of the protein concentration, equal amounts of protein from each rat were added to the gels and transferred onto polyvinylidene fluoride (PVDF) membranes after electrophoresis. After the transfer of proteins, the PVDF membrane was blocked with 5% dry milk and incubated with primary antibodies (phosphorylated-AKT1, phosphorylated-eNOS, Bax, Bcl-xL, and cleaved caspase-3) (Cell Signaling Technology, USA). The incubated membrane was washed with PBS then incubated with a horseradish peroxidase-conjugated antibody (Santa Cruz Biotechnology, Santa Cruz, USA). The bands on the membrane were visualized with enhanced chemiluminescence developing solutions and quantified using ImageJ software.

Statistical analysis

The data of this study are presented as the means ± SD. The data were analyzed using analysis of variance (ANOVA) in SPSS 19.0 (SPSS, Chicago, IL, USA). The difference between two groups was calculated using the Bonferroni test. P < 0.05 was considered statistically significant.

Ac2-26 ameliorated neurological function after CPB

Compared to the sham group, the neurological score in the CPB group was significantly higher. Compared to CPB, Ac2-26 notably up-regulated the score, and AKT1 interference RNA reduced this up-regulation of neurological score (Figure 1).

Ac2-26 improved the blood‒brain barrier after CPB

After CPB, the (wet weight – dry weight)/weight ratio notably increased in the CPB group and decreased by Ac2-26 in the Ac group. The AKT1 interference RNA reduced the improvement in brain edema (Figure 2A).

S100β and NSE levels in the brain were also tested using commercial ELISA kits. After CPB, S100β and NSE increased significantly in the CPB group and decreased by Ac2-26. The Ac2-26-induced decrease in S100β and NSE was partially reduced by AKT1 interference RNA (Figure 2B and C).

Ac2-26 mitigated the pathological brain injury

Figure 3A shows the normal hippocampal neurons, which exhibited clear boundaries and a normal structure in the sham group. Compared to the sham group, Figure 3B presents typical brain injuries, such as cellular degeneration and abnormal cell arrangements, in the CPB group. Compared to the CPB group, Ac2-26 significantly alleviated the pathological injury in the Ac group, but the AKT1 interference RNA was notably reversed the Ac2-26-induced effects (Figure 3).

Ac 2-26 improved neuronal survival

Compared to the sham group, neuronal survival in the hippocampal CA1 region was significantly decreased in the CPB group. Compared to the CPB group, Ac2-26 significantly improved neuronal survival, but the AKT1 interference RNA significantly reduced the Ac2-26-induced improvement in neuronal survival (P < 0:05) (Figure 4A).

Few apoptotic cells were detected in the sham group. Compared to the sham group, the number of apoptotic cells was notably increased in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly decreased the number of positive cells in the hippocampus, but the AKT1 interference RNA partially reversed this decrease (Figure 4B).

We also detected apoptotic proteins in the brain. Ac2-26 inhibited the pro-apoptotic proteins Bax and cleaved caspase-3 but increased Bcl-xL in brain tissue. The AKT1 interference RNA attenuated the regulation of apoptotic proteins by Ac2-26 (Figure 5).

After CPB, AKT1 and eNOS were decreased in the CPB group but increased by Ac2-26. The Ac2-26-induced promotion of AKT1 and eNOS was reduced by the shRNA (Figure 5).

Ac2-26 inhibited local and systemic inflammation after CPB

After CPB, TNF-α, IL-1β, IL-6, and IL-10 were significantly increased in the serum and brain. Ac2-26 reduced TNF-α, IL-1β and IL-6 but upregulated IL-10 in the Ac group. However, the AKT1 RNA interference partially reversed the regulatory effect of Ac2-26 on inflammatory cytokines (Figure 6A and B).

The results of the present study indicated that Ac2-26 reduced local and systemic inflammation, decreased S100β and NSE in the brain, and improved cerebral function after CPB. We also found that Ac2-26 reduced brain pathological injury and ameliorated CPB-induced brain apoptosis and pyroptosis. The protective effect of Ac2-26 on brain injury after CPB may be associated with the promotion of AKT1/eNOS.

CPB is an essential life supporting technique for cardiac surgery. However, CPB induces systemic inflammation and cerebral ischemia that lead to severe brain injury, which is characterized by postoperative cognitive dysfunction, delirium, and stroke [12, 23]. Postoperative brain injury after CPB is strongly associated with short- and long-term outcomes[7], such as prolonged ICU and hospital stays, morbidity and mortality[2, 24].

The present study assessed the neurological score, investigated the brain (wet weight – dry weight)/weight ratio and levels of S100β and NSE in serum, and examined HE staining to evaluate the effect of Ac2-26 on brain injury after CPB. The results indicated that Ac2-26 significantly improved postoperative neurofunction and the blood–brain barrier and reduced pathological injury. These results suggested that Ac2-26 notably reduced brain injury after CPB, which is consistent with previous studies[15, 25].

Although the exact mechanism of postoperative brain injury after CPB is not clear, local ischemia reperfusion injury and SIRS are crucial[10, 11]. During CPB, contact of blood with artificial surfaces activates proinflammatory cells, and these cells further release inflammatory cytokines, including TNF-α, IL-1β, and IL-6. These cytokines infiltrate into the blood‒brain barrier and damage brain tissue[26]. During CPB, the activated microglia also produce many cytokines that contribute to brain injury in combination with SIRS[15]. The severity of inflammation was strongly associated with the expression of S100-𝛽 protein. Ashraf et al. [35] found that IL-6 strongly promoted the expression of S100-𝛽 during the CPB procedure[27]. When the local or systemic inflammation disrupts the blood-brain barrier, significant S100-𝛽 and NSE is released into peripheral blood. Therefore, the levels of S100-𝛽 and NSE in peripheral blood are sensitive to brain injury[28] and are generally regarded as specific markers of brain injury[29, 30].

Ac2-26 improved the neurological score in the present study, down-regulated S100-𝛽 and NSE levels in serum, and reduced pathological injury. These results suggested that Ac2-26 significantly attenuated brain injury after CPB. The protective effect of Ac2-26 on brain injury may be associated with anti-inflammation. The present study detected the concentrations of inflammatory factors in the brain and serum. We found that Ac2-26 down-regulated the proinflammatory factors and up-regulated the anti-inflammatory factor IL-10. These results are consistent with previous studies[15, 17]. The anti-inflammatory effect of Ac2-26 was attributed to the inhibition of NF-κB[13, 17]. During CPB, the NF-κB of endothelial cells and microglia was activated and promoted the secretion of inflammatory factors into brain tissue and the peripheral blood, which ultimately contributed to local and systemic inflammation. However, the activated peptide of annexin A1, Ac2-26, inhibited the activity and phosphorylation of NF-κB[13, 15, 17] and reduced the production of cytokines. The anti-inflammatory effect of Ac2-26 was also associated with the promotion of IL-10. As an important anti-inflammatory factor, IL-10 inhibits the synthesis of proinflammatory cytokines, including TNF-α, IL-1β and IL-6[31].

During CPB, the brain tissue generally undergoes lower perfusion [10], which results in an oxidative stress response. The brain oxidative stress response and local ischemia lead to hippocampal apoptosis[32]. During CPB, apoptosis also plays a crucial role in the pathology of CPB-induced brain injury [33]. The results of the present study suggested that Ac2-26 significantly reduced apoptosis after CPB, and this result was consistent with previous studies[16, 17]. The antiapoptotic effect of Ac2-26 may be due to its regulation of Bax and Bcl-2. The Bcl-2 family, which is primarily composed of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax, regulates apoptosis under pathological conditions. Bax is an important pro-apoptotic protein[34] that promotes the activation of caspase 3, and Bcl-2 is an anti-apoptotic protein that prevents Bax activation and inhibits the cleavage of caspase 3[35]. Caspase-3 is a key enzyme in apoptosis, and cleaved caspase-3 activated by Bax is the specific executor of apoptosis[36]. Ac2-26 decreased the expression of Bax but promoted the expression of Bcl-2, which further inhibited the activation of caspase-3 in brain tissue and reduced apoptosis.

Our previous studies associated the protective effect of Ac2-26 on lung ischemia-reperfusion injury and brain injury-induced cardiac arrest with the promotion of eNOS [16, 17]. The main biological effect of AKT1 is regulating the production of eNOS and cellular proliferation, migration, and survival of the endothelium[37]. Therefore, we hypothesized that the therapeutic effect of Ac2-26 on brain injury after CPB was also attributed to the promotion of AKT1. The present study found that AKT1 shRNA significantly mitigated the protective effect of Ac2-26. These results suggested that the Ac2-26-mediated reduction in CPB-induced lung injury primarily depended on AKT1.

Based on these results, we concluded that Ac2-26 reduced CPB-induced brain injury, and the protective effect of Ac2-26 primarily depended on the promotion of AKT1.

The present study administered shRNA to inhibit the expression of AKT1. However, the shRNA interfered with cerebral and inflammatory cells. This effect may interfere with the conclusion of apoptosis because we know that annexin A1 promotes the apoptosis of inflammatory cells. Our future experiments will explore the mechanism of Ac2-26 on CPB-induced cerebral cell apoptosis using a single-cell model.

CPB (Cardiopulmonary bypass)

SIRS (systemic inflammatory response syndrome)

PVDF (polyvinylidene fluoride)

ANOVA (analysis of variance)

NSE (neuron-specific enolase)

eNOS (Endothelin nictric oxide synthase)

Ethics approval and consent to participate

The Institutional Animal Care and Use Committee of Harbin Medical University and The Medical Ethics Committee of The Second Affiliated Hospital of Harbin Medical University approved this study.

All methods were carried out in accordance with relevant guidelines and regulations.

Methods are reported in accordance with ARRIVE guidelines for the reporting of animal experiments.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

There is no interest or conflict in this article.

Funding

This study was supported by grants from the Heilongjiang Natural Science Foundation (YQ2019H009).

Authors' contributions

All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript; Xue-yong ZHANG, Zi-wei ZOU, Bao-wei JIA and Ziying Liu conducted the experiments, Xi-kun SUN, Lin QIU and Wei GAO wrote the manuscript.

Acknowledgements

Not applicable

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Ac 2-26 reduced pyroptosis to ameliorate the cerebral injury in rats after cardiopulmonary bypass via the AKT1-eNOS pathway

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