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Published on: May 3, 2024
Molecular pathways in sepsis-induced cardiomyocyte pyroptosis: Novel finding on long non-coding RNA
Li An1, Tianyu Yang2, Yi Zhong3
1Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China; Institute of Anesthesia, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.
Objective:
ZNFX1 antisense RNA1 (ZFAS1) has been emerged as a tumor oncogene or suppressor. However, understanding the biological role and underlying molecular mechanism of ZFAS1 in sepsis induced myocardial injury (SIMI) requires more evidence. This study was assigned to probe the effect of lncRNA ZFAS1 on sepsis-induced pyroptosis in cardiomyocytes and its underlying mechanism.
Methods:
Serums of 22 patients with sepsis-induced myocardial injury (SIMI) and 24 healthy controls were collected to determine the expression levels of ZFAS1 and miR-138-5p. Cardiomyocytes (H9C2) or rats were treated by lipopolysaccharide (LPS) to establish in vivo and in vitro sepsis models. H&E staining was applied to observe myocardial injury of rats. The interactions between ZFAS1 and miR-138-5p as well as miR-138-5p and SESN2 were determined by dual-luciferase reporter gene assay and RNA pull-down assay. TUNEL staining was applied to inspect apoptosis level and CCK-8 to measure cell viability. The mRNA levels of ZFAS1, miR-138-5p and SESN2 were measured by qRT-PCR, while the protein expressions of SESN2 and pyroptosis-related proteins (Caspase-1, ASC and NLRP3) were assessed by Western blotting. Levels of inflammatory factors (TNF-α, IL-1β, IL-6 and IL-18) were evaluated by ELISA.
Results:
Patients with SIMI had suppressed ZFAS1 and increased miR-138-5p expression when compared with those in healthy controls. LPS treatment in rats triggered myocardial injury accompanied by interstitial edema and moderate inflammatory cell infiltration. Besides, LPS caused elevated cell apoptosis rate and enhanced cell pyroptosis and inflammation in sepsis cell models. However, ZFAS1 overexpression or SESN2 overexpression in LPS induced rats and in H9C2 cells had meliorated myocardial injury and inflammatory response, indicating that ZFAS1 and SESN2 can inhibit sepsis-induced pyroptosis of cardiomyocytes. MiR-138-5p is a target gene of ZFAS1, while miR-138-5p can negatively mediate SESN2. ZFAS1 alleviated sepsis induced cardiomyocyte pyroptosis by exerting competing endogenous RNA (ceRNA) function to indirectly regulate SESN2, which evidenced by loss and gain functions of ZFAS1 and SESN2.
Conclusion:
LncRNA ZFAS1 serves as a ceRNA of miR-138-5p to up-regulate the expression of SESN2, thereby ameliorating sepsis-induced cardiomyocyte pyroptosis.
Insights
Long non-coding RNA ZFAS1 protects against sepsis-induced myocardial injury by inhibiting pyroptosis. ZFAS1 acts as a competing endogenous RNA to regulate SESN2 expression, reducing cardiomyocyte damage.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Sepsis Pathophysiology
Background:
- Sepsis-induced myocardial injury (SIMI) is a critical complication of sepsis, characterized by cardiomyocyte dysfunction and inflammation.
- The precise molecular mechanisms underlying SIMI, particularly the role of long non-coding RNAs (lncRNAs), remain incompletely understood.
- ZNFX1 antisense RNA1 (ZFAS1) has shown dual roles in cancer, but its function in SIMI requires further investigation.
Purpose of the Study:
- To investigate the role of lncRNA ZFAS1 in sepsis-induced pyroptosis of cardiomyocytes.
- To elucidate the underlying molecular mechanism of ZFAS1 in SIMI.
Main Methods:
- Serum samples from SIMI patients and healthy controls were analyzed for ZFAS1 and miR-138-5p expression.
- In vivo (rat) and in vitro (H9C2 cell) sepsis models were established using lipopolysaccharide (LPS).
- Molecular interactions were assessed using dual-luciferase reporter and RNA pull-down assays; pyroptosis, apoptosis, and inflammation markers were quantified.
Main Results:
- SIMI patients exhibited decreased ZFAS1 and increased miR-138-5p expression compared to controls.
- LPS treatment induced myocardial injury, pyroptosis, and inflammation in vivo and in vitro.
- ZFAS1 and SESN2 overexpression ameliorated myocardial injury and inflammatory responses in LPS-treated models.
- ZFAS1 functions as a competing endogenous RNA (ceRNA) for miR-138-5p, indirectly upregulating SESN2.
Conclusions:
- LncRNA ZFAS1 protects cardiomyocytes against sepsis-induced pyroptosis.
- ZFAS1 acts as a ceRNA targeting miR-138-5p to upregulate SESN2 expression, thereby mitigating SIMI.
- ZFAS1 represents a potential therapeutic target for managing sepsis-induced myocardial injury.
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