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LGR4 silence aggravates ischemic injury by modulating mitochondrial function and oxidative stress via ERK signaling
Tao Chen1, Xiangrui Qiao1, Lele Cheng1
1Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.
Insights
Leucine-rich repeat domain containing G protein-coupled receptor 4 (LGR4) protects against heart injury. LGR4 regulates mitochondrial dysfunction and oxidative stress via ERK signaling, offering a potential therapeutic target for myocardial ischemia-reperfusion injury.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Leucine-rich repeat domain containing G protein-coupled receptor 4 (LGR4) is vital for organ function, but its role in myocardial ischemia-reperfusion (I/R) injury is unclear.
- Myocardial I/R injury is a significant clinical concern with limited therapeutic options.
Purpose of the Study:
- To investigate the function and mechanism of LGR4 in myocardial I/R injury.
- To explore LGR4's role in regulating cellular processes and signaling pathways during I/R.
Main Methods:
- Established an in vitro I/R injury model using H9c2 cells.
- Assessed LGR4 expression, cell apoptosis, oxidative stress markers (ROS, MDA, SOD), and mitochondrial function (ATP, cyt c).
- Investigated the involvement of the ERK signaling pathway and LGR4's interaction with it.
Main Results:
- I/R injury upregulated LGR4 expression in H9c2 cells.
- LGR4 knockdown exacerbated apoptosis, oxidative stress, and mitochondrial dysfunction.
- LGR4 silencing inhibited ERK pathway activation, which could be partially reversed by an ERK activator.
Conclusions:
- LGR4 plays a protective role in myocardial I/R injury.
- LGR4 modulates mitochondrial dysfunction and oxidative stress through the ERK signaling pathway.
- LGR4 represents a potential therapeutic target for mitigating cardiac I/R injury.
Abstract:
It is reported that LGR4 (leucine-rich repeat domain containing G protein-coupled receptor 4) plays a crucial role in the physiological function of many organs. However, few data are available on the function and mechanism of LGR4 in myocardial ischemia-reperfusion (I/R) injury. The aim of this study was to explore the function and mechanism of LGR4 in I/R injury. We incubated H9c2 cells in simulating ischemia buffer and then re-incubated them in normal culture medium to establish a model of I/R injury in vitro. The expression of LGR4 was evaluated by RT-PCR and western blot. Besides, the cell apoptosis was evaluated by flow cytometric analysis and the content of ROS, SOD, MDA, LDH, CK, ATP, cyt c were detected by special commercial kits. The expression of mitochondrial function-related proteins were detected by western blot. Then, the roles of ERK signaling pathway was determined with TBHQ (ERK activator) treatment. Our data have demonstrated that I/R boosted the expression of LGR4 in H9c2 cells. Knockdown of LGR4 increased the apoptosis rate of H9c2 cells and led to excessed oxidant stress and impaired mitochondrial function by increasing the levels of ROS, MDA, LDH, CK and cyt c and inhibiting SOD activity, ATP production. In addition, LGR4 silence inhibited the activation of ERK pathway. And TBHQ partially reversed the effects of LGR4 knockdown on H9c2 cells. To conclude, our study indicated that LGR4 regulated mitochondrial dysfunction and oxidative stress by ERK signaling pathways, which provides a potential cardiac protective target against I/R.
