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Hyperglycemic Conditions Prime Cells for RIP1-dependent Necroptosis
Timothy J LaRocca1, Sergey A Sosunov2, Nicole L Shakerley1
1From the Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208.
The Journal of Biological Chemistry
|May 1, 2016
Summary
High glucose levels enhance necroptosis, a programmed cell death pathway dependent on RIP1 kinase. This finding suggests hyperglycemia increases susceptibility to cell death and exacerbates injuries like brain hypoxia-ischemia.
Area of Science:
- Cell Biology
- Immunology
- Pathology
Background:
- Necroptosis is a distinct programmed cell death (PCD) pathway regulated by RIP1.
- Glycolysis supports necroptosis effectors like advanced glycation end products (AGEs) and reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the effect of hyperglycemia on necroptosis.
- To determine if high glucose levels alter programmed cell death pathways.
Main Methods:
- Primary red blood cells, Jurkat T cells, and U937 monocytes were exposed to hyperglycemic glucose levels.
- RIP1 inhibition was used to confirm necroptosis dependence.
- Protein levels of RIP1, RIP3, and MLKL were analyzed.
- A mouse model of brain hypoxia-ischemia injury was employed.
Main Results:
- Hyperglycemia significantly enhanced RIP1-dependent necroptosis in tested cell types.
- Increased RIP1, RIP3, and MLKL protein levels were observed in nucleated cells, independent of transcriptional regulation.
- High glucose inhibited extrinsic apoptosis, shifting the PCD balance towards necroptosis.
- Hyperglycemia exacerbated brain hypoxia-ischemia injury in mice, which was mitigated by necroptosis inhibition.
Conclusions:
- Hyperglycemia primes cells for necroptosis, increasing susceptibility to cell death.
- Local glucose concentrations can modulate the balance between different PCD pathways.
- Glucose-mediated effects on PCD have implications for clinical outcomes and disease exacerbation.
Keywords:
Fas ligandapoptosisdiabetesglucosehyperglycemiaischemianecroptosisnecrosis (necrotic death)programmed cell deathtumor necrosis factor (TNF)More Related Videos
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