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MicroRNA-135a is up-regulated and aggravates myocardial depression in sepsis via regulating p38 MAPK/NF-κB pathway
Ge Zheng1, Minli Pan1, Weimin Jin1
1Department of Pediatrics, Ruian People's Hospital, Ruian, Zhejiang 325200, China.
Abstract:
MicroRNA-135a (miR-135a) is implicated in the pathological processes of several cancers. However, the roles and regulatory mechanism of miR-135a in sepsis-induced myocardial depression (MD) remain largely unknown. In this study, the serum of patients with sepsis and healthy controls was obtained. The miR-135a expression was then measured. Then lentiviruses (miR-135a mimic, inhibitor and scramble control) were transfected into BALB/c mice. After 4days of transfection, polymicrobial sepsis model was established by cecal ligation and puncture (CLP) surgery. The serum tumor-necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 were detected. Cardiac function was assessed. In addition, the protein expressions of p38 MAPK/NF-κB pathway-related proteins were determined. Besides, SB203580 and JSH-23, the inhibitors of p38 MAPK and NF-κB respectively, were used to treat the isolated ventricular myocytes in vitro. MiR-135a was significantly up-regulated in the serum of patients with sepsis. In comparison with CLP group, the concentrations of TNF-α, IL-1β and IL-6 and the expressions of p-p38 and p-p65 in CLP+miR-135a mimic group were significantly increased, while markedly decreased in CLP+miR-135a inhibitor group. Moreover, EF, FS, LVdP/dt (max), LVdP/dt (min) and LVDP of CLP+miR-135a mimic group were all significantly decreased, while markedly increased in CLP+miR-135a inhibitor group. Besides, the increased expressions of p-p38 and p-p65, decreased expression of p-IKBα and the decreased percentage of contraction amplitude in miR-135a mimic group were markedly reversed by SB203580 or JSH-23 treatments. Up-regulation of miR-135a could aggravate sepsis-induced inflammation and myocardial dysfunction via activation of p38 MAPK/NF-κB pathway.
Insights
MicroRNA-135a (miR-135a) exacerbates sepsis-induced myocardial depression by activating the p38 MAPK/NF-κB pathway, increasing inflammation and impairing cardiac function. Inhibiting miR-135a shows therapeutic potential.
Area of Science:
- Molecular Biology
- Cardiology
- Immunology
Background:
- Sepsis-induced myocardial depression (MD) is a critical complication of sepsis.
- The role of microRNA-135a (miR-135a) in sepsis-related MD is not well understood.
- Previous studies link miR-135a to cancer pathology.
Purpose of the Study:
- To investigate the role and regulatory mechanism of miR-135a in sepsis-induced MD.
- To explore the involvement of the p38 MAPK/NF-κB pathway in miR-135a's effects on MD.
Main Methods:
- Serum miR-135a levels were measured in sepsis patients and healthy controls.
- Mice were transfected with miR-135a mimic or inhibitor before inducing sepsis via cecal ligation and puncture (CLP).
- Cardiac function, inflammatory cytokine levels (TNF-α, IL-1β, IL-6), and p38 MAPK/NF-κB pathway protein expressions were assessed. In vitro studies used pathway inhibitors.
Main Results:
- miR-135a was significantly upregulated in sepsis patients' serum.
- Overexpression of miR-135a in mice worsened sepsis-induced inflammation and cardiac dysfunction, increasing p38 MAPK/NF-κB pathway activation.
- Inhibition of miR-135a ameliorated these effects, and pathway inhibitors reversed miR-135a mimic-induced cardiac dysfunction.
Conclusions:
- Upregulated miR-135a aggravates sepsis-induced inflammation and myocardial dysfunction.
- The p38 MAPK/NF-κB pathway is a key mechanism mediating miR-135a's detrimental effects in sepsis-induced MD.
- Modulating miR-135a may offer a therapeutic strategy for sepsis-induced myocardial depression.
