Exploration of MST1-Mediated Secondary Brain Injury Induced by Intracerebral Hemorrhage in Rats via Hippo Signaling Pathway
Intracerebral hemorrhage (ICH) is a serious public health problem which causes high rates of disability and mortality in adults. Cell apoptosis is a sign of secondary brain injury (SBI) following ICH. Mammalian sterile 20-like kinase-1 (MST1), an apoptosis-promoting kinase, is a part of the Hippo signaling pathway and involved in cell death, oxidative stress, and inflammation. However, the role and underlying mechanism of MST1 in SBI induced by ICH have not yet been fully explained. The main purpose of present research was to explore the role of MST1 and its potential mechanism in SBI after ICH. An ICH model was established by injecting autologous blood into the right basal ganglia in male SD rats. We found that MST1 phosphorylation was significantly increased in brain tissues of rats after ICH. Additionally, inhibition of MST1 phosphorylation by a chemical inhibitor (Xmu-mp-1) and genetic knockdown could effectively reduce the activation of P-LATS1 and P-YAP which are downstream proteins of MST1 and decrease neuronal cell death and inflammation reaction in ICH rats. Furthermore, the decreased of MST1 phosphorylation reduced brain edema, blood-brain barrier (BBB) damage, and neurobehavioral impairment during ICH. Over-expression of MST1 resulted in opposite effects. Finally, deletion of MST1 significantly reduced neuronal apoptosis in vitro. In summary, our study revealed that MST1 played an important role in the SBI following ICH, and inhibition of MST1 could alleviate ICH-induced SBI. Therefore, MST1 may be considered as a potential therapeutic target for SBI following ICH.
KeywordsMST1 Intracerebral hemorrhage Secondary brain injury Neuronal apoptosis
This study was funded by the National Key R&D Program of China (No. 2018YFC1312600 and 2018YFC1312601), Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Jiangsu Provincial Medical Youth Talent (No. QNRC2016728), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), and Suzhou Government (LCZX201601).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
- 4.Bobinger T, Burkardt P, Huttner HB, Manaenko A. Programmed cell death after intracerebral hemorrhage. Curr Neuropharmacol. 2017.Google Scholar
- 26.Wang Z, Zhou F, Dou Y, Tian X, Liu C, Li H, et al. Melatonin alleviates intracerebral hemorrhage-induced secondary brain injury in rats via suppressing apoptosis, inflammation, oxidative stress, DNA damage, and mitochondria injury. Transl Stroke Res. 2017.Google Scholar
- 36.Nakamura M, Zhai P, Del Re DP, Maejima Y, Sadoshima J. Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. JCI Insight. 2016;1(5).Google Scholar