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Published on: March 12, 2018
Mechanism of programmed cell death factor 4/nuclear factor-κB signaling pathway in porcine coronary
Qiang Su1, Lang Li2, Jiangyou Wang1
1Department of Cardiology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Abstract:
The aim of this study was to investigate the role of the programmed cell death factor 4 (PDCD4)/nuclear factor-κB (NF-κB) signaling pathway in coronary micro-embolism (CME)-induced inflammatory responses and cardiac dysfunction in a porcine model. Bama miniature pigs were randomly divided into four groups (n = 5 per group). Micro-embolization balls or saline were infused through a microcatheter in the left anterior descending (LAD) artery in the CME and Sham groups, respectively. PDCD4 siRNA or control siRNA mixed with transfection reagent was infused via the LAD artery 72 h before CME induction in the CME + siRNA-PDCD4 and siRNA-control groups, respectively. Cardiac function was evaluated with ultrasound. Tissue biopsy was stained with hematoxylin-eosin (HE) and hematoxylin basic fuchsin picric acid (HBFP) to measure infarction area. Myocardial PDCD4 and tumor necrosis factor-α (TNF-α) mRNA and protein expression were analyzed by quantitative PCR and Western blotting. NF-κB activity was evaluated in gel electrophoretic mobility shift assay. Echocardiographic parameters showed that compared with the sham group, the CME group had impaired heart function, manifested as systolic dysfunction and left ventricular dilatation (reduced left ventricular ejection fraction [LVEF], left ventricular fractional shortening [FS], and cardiac output [CO] [P < 0.05] and increased left ventricular end-diastolic diameter [LVEDd] [P < 0.05]). Compared with the CME group, the CME + siRNA-PDCD4 group had attenuated CME-induced cardiac function damage (increased LVEF, FS and CO [P < 0.05] and reduced LVEDd [P < 0.05]). Compared with the sham group, the CME group had significantly increased PDCD4 and TNF-α mRNA and protein expression and increased NF-κB activity (P < 0.05). These effects were significantly inhibited in the CME + siRNA-PDCD4 group (P < 0.05). In conclusion, PDCD4/NF-κB signaling pathway activation is an important mechanism for CME-induced cardiac dysfunction, suggesting that inhibition of PDCD4/NF-κB signaling pathway may be a potential target for the prevention and treatment of CME.
Insights
The programmed cell death factor 4 (PDCD4)/nuclear factor-κB (NF-κB) pathway drives cardiac dysfunction after coronary micro-embolism (CME). Inhibiting this PDCD4/NF-κB signaling pathway may offer a therapeutic strategy for CME.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Inflammation Research
Background:
- Coronary micro-embolism (CME) causes significant cardiac dysfunction and inflammatory responses.
- The precise molecular mechanisms underlying CME-induced myocardial injury remain incompletely understood.
- Identifying key signaling pathways involved in CME pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of the programmed cell death factor 4 (PDCD4)/nuclear factor-κB (NF-κB) signaling pathway in CME-induced cardiac dysfunction and inflammation.
- To evaluate the therapeutic potential of inhibiting the PDCD4/NF-κB pathway in a porcine model of CME.
Main Methods:
- A porcine model of CME was established by infusing micro-embolization balls into the left anterior descending artery.
- PDCD4 expression was inhibited using small interfering RNA (siRNA) delivered via the left anterior descending artery.
- Cardiac function was assessed using echocardiography, and myocardial tissue was analyzed for infarction, PDCD4 and TNF-α expression, and NF-κB activity.
Main Results:
- CME induction led to impaired cardiac function, characterized by reduced ejection fraction and cardiac output, and increased left ventricular end-diastolic diameter.
- CME significantly increased myocardial PDCD4 and TNF-α expression and elevated NF-κB activity.
- Inhibition of PDCD4 using siRNA attenuated CME-induced cardiac dysfunction and inflammatory markers.
Conclusions:
- Activation of the PDCD4/NF-κB signaling pathway is a critical mechanism contributing to cardiac dysfunction following coronary micro-embolism.
- Targeting the PDCD4/NF-κB pathway presents a promising therapeutic strategy for preventing and treating CME-induced myocardial injury.
