Developing a Novel Pharmacotherapy to Target the Inflammatory Contribution of Cardiovascular Disease

Abstract

Over the past three decades, the implementation on secondary preventive strategies has reduced the global burden of cardiovascular disease (CVD). Despite this, recent years have seen a gradual increase in age-standardised risk and mortality from CVD, largely driven by the rising prevalence of metabolic disorders. Under these circumstances, there has been a refocusing on novel biological pathways to identify potential therapeutic strategies beyond traditional approaches. One potential candidate is the P2X purinoceptor 7 (P2X7R), a non-selective ATP-gated cation channel that mediates the influx of sodium and calcium ions and the efflux of potassium. The receptor is activated by high concentrations of extracellular adenosine-5’-triphosphate, which is released in response to cellular injury. This activation leads to the formation of a large, non-selective pore, resulting in sustained activation of the NOD- LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. This complex plays a key role in the mechanisms required for the maturation and release of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β). Compared to traditional immunomodulatory compounds that may lead to immunosuppressive effects, targeting the P2X7R offers several advantages. Given that the receptor is specifically activated in response to sterile injury, inhibiting the P2X7R would help preserve immune mechanisms essential for host-defence. These properties make the P2X7R a promising therapeutic target in CVD, potentially paving the way for a novel therapeutic strategy. This thesis underscores the potential of P2X7R antagonists as a novel therapeutic strategy for CVD. Through the comprehensive use of patient-derived cells for pharmacological evaluation, in combination with risk stratification and preclinical evaluation, these findings provide a strong foundation for the development of P2X7R antagonists and offers a promising alternative treatment for CVD.