P2X7 Receptors: An Untapped Target for the Management of Cardiovascular Disease
Brandon G Shokoples1, Pierre Paradis1, Ernesto L Schiffrin1,2
1Vascular and Hypertension Research Unit, Lady Davis Institute for Medical Research (B.G.S., P.P., E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Abstract:
Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.
Insights
Targeting the P2X7 receptor, a key mediator of inflammation, shows promise for treating cardiovascular diseases. Blocking P2X7 reduces inflammation and disease severity in preclinical models, offering a potential new therapeutic strategy.
Area of Science:
- Cardiovascular Research
- Inflammation Biology
- Purinergic Signaling
Background:
- Chronic low-grade inflammation is a significant contributor to cardiovascular diseases.
- Current anti-inflammatory strategies for cardiovascular disease are limited.
- The P2X7 receptor plays a critical role in mediating inflammation and cellular death.
Purpose of the Study:
- To explore the role of the P2X7 receptor in cardiovascular disease pathogenesis.
- To evaluate the therapeutic potential of P2X7 antagonism in cardiovascular disorders.
Main Methods:
- Investigated P2X7 receptor activation pathways involving extracellular ATP and the NLRP3 inflammasome.
- Examined the effects of P2X7 receptor knockout (KO) and antagonism in animal models of cardiovascular disease.
- Reviewed clinical trial data on IL-1β and IL-18 inhibition in cardiovascular conditions.
Main Results:
- P2X7 activation leads to the release of pro-inflammatory cytokines IL-1β and IL-18, implicated in hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure.
- P2X7 receptor KO mice showed reduced inflammatory responses and disease severity.
- P2X7 antagonism attenuated hypertension and atherosclerosis progression in animal models.
- Inhibition of IL-1β and IL-18 demonstrated efficacy in reducing major adverse cardiac events in clinical trials.
Conclusions:
- The P2X7 receptor is a key mediator in the development of various cardiovascular diseases.
- P2X7 antagonism represents a promising, yet untapped, therapeutic strategy for cardiovascular disorders.
- Available P2X7 antagonists with established safety profiles support further investigation for clinical application.
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