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CIRC_0003907 MODULATES SEPSIS-INDUCED MYOCARDIAL INJURY VIA ENHANCING MYD88/NLRP3/NF-ΚB AXIS BY SPONGING MIR-944
1Hypertension/Heart Failure Ward, Central Hospital Affiliated to Shandong First Medical University, Jinan City, China.
Insights
Circular RNA_0003907 (circ_0003907) exacerbates sepsis-induced cardiomyopathy by sponging microRNA-944 (miR-944), activating the MYD88/NLRP3/NF-κB pathway. Targeting circ_0003907 may offer a novel therapeutic strategy for sepsis-induced heart dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Immunology
Background:
- Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis with high mortality and limited treatment options.
- Understanding the molecular mechanisms underlying SIC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of circular RNA_0003907 (circ_0003907) in the pathogenesis of sepsis-induced myocardial injury.
- To elucidate the molecular interactions involving circ_0003907, microRNA-944 (miR-944), and the MYD88/NLRP3/NF-κB signaling pathway in sepsis.
Main Methods:
- An in vitro cardiomyocyte injury model was established using lipopolysaccharide (LPS) on human AC16 cells.
- Quantitative real-time PCR, cell proliferation and apoptosis assays, ELISA, western blot, dual-luciferase reporter, and RNA immunoprecipitation assays were employed.
- Expression levels of circ_0003907, miR-944, MYD88, and downstream signaling molecules were analyzed.
Main Results:
- Circ_0003907 expression was upregulated in SIC patients' serum and LPS-treated cardiomyocytes.
- Knockdown of circ_0003907 attenuated LPS-induced cardiomyocyte dysfunction, including inhibited proliferation, increased apoptosis, inflammation, and oxidative stress.
- Circ_0003907 acted as a molecular sponge for miR-944, upregulating MYD88 expression and activating the MYD88/NLRP3/NF-κB pathway.
Conclusions:
- Circ_0003907 aggravates sepsis-induced cardiomyocyte injury by sponging miR-944 and activating the MYD88/NLRP3/NF-κB axis.
- Circ_0003907 represents a potential therapeutic target for sepsis-induced cardiomyopathy.
Abstract:
Background : Sepsis-induced cardiomyopathy ( SIC ) is a common complication of sepsis with high morbidity and mortality but lacks specific therapy. The purpose of this study was to investigate the role of circularRNA_0003907 (circ_0003907) in myocardium injury induced by sepsis. Methods: In this experiment, human AC16 cells were treated with lipopolysaccharide (LPS) to induce an in vitro cardiomyocyte injury model. Expression of circ_0003907, microRNA-944 (miR-944), and MYD88 was detected using quantitative real-time polymerase chain reaction. Cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, thymidine analog 5-ethynyl-2'-deoxyuridine, and flow cytometry assays. Secretions of proinflammatory cytokines IL-6 and TNF-α were detected using ELISA kits. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were detected using special kits. Protein levels of cyclin D1, cleaved caspase-3, MYD88, NLRP3, P65, and IκBα were determined using western blot assay. After being predicted using Circineractome and starBase, the interaction between miR-944 and circ_0003907 or MYD88 was confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0003907 expression was increased in serum from SIC patients and in LPS-treated AC16 cells. Circ_0003907 knockdown might abolish LPS-triggered proliferation inhibition, and the promotion of apoptosis, inflammatory response, and oxidative stress in AC16 cells. In mechanism, circ_0003907 acted as a sponge for miR-944 to increase MYD88 expression. Meanwhile, the absence of circ_0003907 induced miR-944 expression and suppressed MYD88/NLRP3/NF-κB levels. Conclusion: Circ_0003907 sponged miR-944 to aggravate LPS-induced AC16 cell dysfunction via activating the MYD88/NLRP3/NF-κB axis during sepsis, which might provide a new direction for the treatment of SIC .
