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Published on: January 20, 2023
Prostacyclin-dependent apoptosis mediated by PPAR delta
1Department of Pharmacology, National Cardiovascular Center Research Institute, Fujishiro-dai, Suita, Osaka 565-8565, Japan.
The Journal of Biological Chemistry
|September 12, 2001
Summary
Intracellular prostacyclin (PGI(2)) promotes apoptosis by activating peroxisome proliferator-activated receptor delta (PPARδ). Extracellular PGI(2) and cAMP reduce apoptosis, revealing a novel signaling pathway for cell fate control.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Prostacyclin (PGI(2)) is a key regulator of hemostasis, acting as a vasodilator and inhibiting platelet aggregation.
- PGI(2) exerts its canonical functions via the IP receptor, a G protein-coupled receptor that increases intracellular cyclic AMP (cAMP) levels.
Purpose of the Study:
- To investigate the distinct roles of intracellular versus extracellular prostacyclin in cellular apoptosis.
- To elucidate the signaling pathways involved in prostacyclin-mediated apoptosis, particularly the involvement of peroxisome proliferator-activated receptor delta (PPARδ).
Main Methods:
- Expressing prostacyclin synthase in human embryonic kidney 293 cells to generate intracellular PGI(2).
- Treating cells with extracellular PGI(2), dibutyryl cAMP, and the cAMP antagonist RpcAMP.
- Utilizing a mutant form of PPARδ (L431A/G434A) to block receptor activation.
Main Results:
- Intracellular PGI(2) significantly promoted apoptosis, mediated by the activation of endogenous PPARδ.
- Extracellular PGI(2) and dibutyryl cAMP exhibited anti-apoptotic effects, reducing cell death.
- The cAMP antagonist RpcAMP enhanced PGI(2)-induced apoptosis, suggesting a complex interplay between cAMP and PPARδ signaling.
- Blocking PPARδ activation with a specific mutant abolished PGI(2)-mediated apoptosis.
Conclusions:
- Prostacyclin can activate a novel, PPARδ-dependent signaling pathway that promotes apoptosis, distinct from its canonical cAMP-mediated effects.
- This discovery reveals a second, critical signaling role for prostacyclin in regulating cell fate.
- Understanding this dual signaling capacity of PGI(2) opens new avenues for therapeutic interventions in diseases involving cell survival and death.
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