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Annexin A1 Mimetic Peptide AC2-26 Inhibits Sepsis-induced Cardiomyocyte Apoptosis through LXA4/PI3K/AKT Signaling
Li Zhang1, Yan-Lei Zheng2, Rong-Hua Hu2
1Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Abstract:
The aim of the present study was to explore the effects of annexin A1 (ANXA1) mimetic peptide AC2-26 on sepsis-induced cardiomyocyte apoptosis in vivo and in vitro and the underlying mechanisms. In the in vivo study, a rat septic model was established by the cecal ligation and puncture (CLP). The rats were divided into control group, sepsis group and AC2-26 group. The rats in the AC2-26 group were intraperitoneally injected with AC2-26 (1 mg/kg) 2 h before CLP, and those in the control group and sepsis group were injected with the same volume of normal saline. The myocardial tissue was examined by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Furthermore, myocardial apoptosis was measured by terminal dUTP nick end-labeling (TUNEL) assay. In the in vitro study, H9C2 cells were cultured and divided into three groups: control group, in which cells were only given the basic culture medium; LPS group, in which cells were treated with 10 μg/mL LPS; AC2-26 group, in which cells were treated with 0.5 μmol/L AC2-26 2 h before 10 μg/mL LPS was given. The apoptosis of H9C2 cells was detected by flow cytometry. The levels of lipoxin A4 receptor (LXA4), phosphoinositide-3-kinase (PI3K) and protein kinase B (PKB or AKT) protein were measured by Western blotting, the activity of NF-κB and the level of TNF-α by ELISA and the activities of caspase-3/8 by using the caspase activity kits. The in vivo study showed that the myocardial pathological damage and myocardial ultrastructural damage were significantly alleviated and the myocardial apoptosis significantly decreased in the AC2-26 group as compared with the sepsis group (P<0.05 for all). The in vivo study revealed that the apoptosis of H9C2 cells was profoundly ameliorated in the AC2-26 group relative to the sepsis group (P<0.05). The protein expression levels of LXA4 were significantly up-regulated, and those of PI3K and AKT prominently down-regulated in the AC2-26 group when compared with those in the LPS group (P<0.05 for all). The activity of NF-κB was greatly inhibited and the level of TNF-α markedly decreased in the AC2-26 group as compared with those in the LPS group (P<0.05 for all). AC2-26 treatment also significantly suppressed the activities of caspase-3/8 in H9C2 cells. In conclusion, these findings suggest that AC2-26 may alleviate the sepsis-induced cardiomyocyte apoptosis in vivo and in vivo through the LXA4/PI3K/AKT signaling pathway.
Insights
Annexin A1 (ANXA1) peptide AC2-26 effectively reduces sepsis-induced heart cell death in rats and cell cultures. This protective effect is mediated by the lipoxin A4 (LXA4) pathway, highlighting AC2-26 as a potential therapeutic agent for sepsis.
Area of Science:
- Cardiovascular Biology
- Sepsis Pathophysiology
- Molecular Medicine
Background:
- Sepsis frequently leads to cardiomyocyte apoptosis, contributing to cardiac dysfunction and mortality.
- Annexin A1 (ANXA1) plays a role in inflammation and cell survival, with its mimetic peptide AC2-26 showing therapeutic potential.
- Understanding the mechanisms by which ANXA1 mimetics affect sepsis-induced cardiac injury is crucial for developing targeted treatments.
Purpose of the Study:
- To investigate the protective effects of the ANXA1 mimetic peptide AC2-26 against sepsis-induced cardiomyocyte apoptosis.
- To elucidate the underlying molecular mechanisms, focusing on the lipoxin A4 (LXA4) signaling pathway.
Main Methods:
- In vivo: Cecal ligation and puncture (CLP) rat model; administration of AC2-26; assessment of myocardial damage via HE staining, TEM, and TUNEL assay.
- In vitro: H9C2 cardiac cells treated with lipopolysaccharide (LPS) and AC2-26; apoptosis measured by flow cytometry.
- Molecular analysis: Western blotting for LXA4, PI3K, AKT; ELISA for NF-κB and TNF-α; caspase activity assays.
Main Results:
- AC2-26 significantly reduced myocardial pathological damage and apoptosis in CLP rats compared to the sepsis group.
- In vitro, AC2-26 markedly ameliorated LPS-induced H9C2 cell apoptosis.
- AC2-26 treatment upregulated LXA4, downregulated PI3K/AKT, inhibited NF-κB and TNF-α, and suppressed caspase-3/8 activities.
Conclusions:
- The ANXA1 mimetic peptide AC2-26 demonstrates significant cardioprotective effects against sepsis-induced apoptosis.
- AC2-26 exerts its protective effects by modulating the LXA4/PI3K/AKT signaling pathway.
- These findings support AC2-26 as a promising therapeutic candidate for sepsis-related cardiac complications.
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