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Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1β Pathway
Junteng Zhou1, Geer Tian2, Yue Quan2
1Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
P2X7 purinergic receptor (P2X7R) has been implicated in several cardiovascular diseases. However, whether it regulates cardiac fibrosis remains elusive. Herein, its involvement in the development of cardiac fibrosis was examined using a transverse aortic constriction (TAC) mice model and cardiac fibroblasts (CFs) hyperstimulated by TGF-β1 for 48 hours. Results showed that TAC and TGF-β1 treatment increased the expression of P2X7R. Silencing of P2X7R expression with siP2X7R ameliorated TGF-β1 effects on fibroblasts activation. Similarly, P2X7R inhibition by Brilliant Blue G (BBG) reduced mRNA and protein levels of profibrosis markers, while the P2X7R agonist BzATP accelerated the TGF-β1-induced CFs activation. Moreover, it was found that TGF-β1-induced CFs activation was mediated by the NLRP3/IL-1β inflammasome pathway. BBG or siP2X7R treatment suppressed NLRP3/IL-1β pathway signaling. In vivo, BBG significantly alleviated TAC-induced cardiac fibrosis, cardiac dysfunction, and NLRP3/IL-1β activation. Collectively, our findings imply that suppressing P2X7R may limit cardiac fibrosis and abnormal activation of CFs.
Insights
The P2X7 purinergic receptor (P2X7R) promotes cardiac fibrosis by activating cardiac fibroblasts via the NLRP3/IL-1β inflammasome pathway. Suppressing P2X7R may offer a therapeutic strategy for cardiac fibrosis.
Area of Science:
- Cardiovascular Research
- Cell Biology
- Immunology
Background:
- The P2X7 purinergic receptor (P2X7R) is linked to cardiovascular diseases.
- Its role in regulating cardiac fibrosis is not well understood.
Purpose of the Study:
- To investigate the role of P2X7R in the development of cardiac fibrosis.
- To explore the underlying mechanisms involving cardiac fibroblasts and the NLRP3/IL-1β inflammasome pathway.
Main Methods:
- Utilized a transverse aortic constriction (TAC) mouse model and TGF-β1-stimulated cardiac fibroblasts (CFs).
- Assessed P2X7R expression, silencing (siP2X7R), and inhibition (Brilliant Blue G - BBG).
- Examined profibrotic markers, CF activation, and the NLRP3/IL-1β inflammasome pathway.
Main Results:
- TAC and TGF-β1 increased P2X7R expression in CFs.
- P2X7R inhibition (BBG) or silencing (siP2X7R) reduced TGF-β1-induced CF activation and profibrotic markers.
- P2X7R activation exacerbated TGF-β1 effects, and the pathway involved NLRP3/IL-1β.
- BBG treatment attenuated TAC-induced cardiac fibrosis, dysfunction, and inflammasome activation.
Conclusions:
- P2X7R plays a critical role in promoting cardiac fibrosis.
- P2X7R mediates cardiac fibroblast activation through the NLRP3/IL-1β inflammasome pathway.
- Targeting P2X7R represents a potential therapeutic approach for mitigating cardiac fibrosis.
