The ATP connection: a new therapeutic promise of P2X7 targeting in hypertension and vascular injury.

While hypertension is traditionally viewed primarily as a hemodynamic disorder, it is now recognized that the immune system plays a fundamental role in its pathogenesis [1]. Elevated blood pressure is associated with abnormal immune responses, including increased levels of pro-inflammatory cytokines and activated immune cells [1], yet our understanding of these interactions remains incomplete [2]. Activated immune cells like T cells, macrophages, and dendritic cells infiltrate the target organs, affecting their function and triggering prohypertensive changes. Such chronic inflammation is linked to vascular dysfunction, renal damage, and the overall progression of hypertension [3]. The mechanisms of triggering the immune responses in hypertension remain, however, unclear. A broad range of prohypertensive factors such as increased sympathetic activity, stress, high salt intake, changes in the microbiome, local oxidative stress, and mechanical forces in blood vessels, can all trigger inflammatory activation. The key specific mechanisms of immune activation in hypertension include antigen-dependent immune activation [1], NLRP3/Inflammasome pathway [1], neuroimmune axis [4], direct immunomodulation by high salt environments [1], and bystander, nonantigen-dependent immune activation [5]. In this context, the role of the P2RX7 gene and its related pathways is particularly intriguing, as it is supported by early genetic association studies. For example, in a white population, the single-nucleotide polymorphism (rs598174) of P2X7 exhibited a robust association with both systolic and diastolic ambulatory blood pressure [6]. P2X7 receptor operates as a ligand-gated cation channel and responds to high levels of extracellular ATP. Indeed, increased ATP concentrations in plasma are noted in hypertensive patients [7]. ATP release induced by hypertension stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. This elevation ostensibly amplifies T-cell reactions in hypertension through a P2X7-dependent pathway [7]. P2X7 activation leads to the assembly and activation of the NLRP3 inflammasome, resulting in the release of proinflammatory cytokines, IL-1beta, and IL-18, capable of stimulating immune responses. The upregulation of P2X7 activation and increased concentrations of IL-1β and IL-18 have been linked to the development of various cardiovascular conditions, including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. Notably, P2RX7 is also required for the generation of long-lived memory CD8+ T cells. These T cells have been associated with sensitization to hypertension development in response to relatively mild hypertensive stimuli. On the other hand, high concentrations of ATP can induce necrotic, pyroptotic, or apoptotic cell death, depending on the stimulus and cell type. This process can further stimulate the immune system via the release of damage-associated molecular patterns (DAMPs) and neoantigens. Apart from its main function in initiating inflammation and cell death, P2X7 also plays a role in processes such as nociception, vascular function, glucose uptake, and even in promoting cell survival [8]. P2X7 activation inherently drives hypertensive processes within the kidney. Angiotensin II (Ang II) and aldosterone increase ATP concentrations within the renal interstitium, which aligns with blood pressure elevation. The activation of P2X7 on the renal vasculature, propelled by this surge in ATP, indices P2X7-mediated constriction of the medullary microcirculation [9], inciting regional hypoxia, fostering vascular hypertrophy and renal inflammation [9]. Thus, the potential value of P2X7 targeting in hypertension, lies in its pleiotropic effects at the interface of immunity/inflammation and metabolic regulation in hypertension (Fig. 1). The activation of P2RX7 promotes mitochondrial homeostasis and metabolic function, suggesting that antagonism or knockout of P2RX7 could attenuate this response.FIGURE 1: Pleiotropic effects of P2X7 receptor in hypertension. NLRP3, NLR family pyrin domain containing 3; Tem, effector memory T cells. Created using Biorender.com.In the current issue of the Journal of Hypertension, Schiffrin's lab provides further compelling evidence for the role of P2X7 in hypertension and its potential as a therapeutic target [10]. Authors utilize several independent approaches ranging from an animal model of hypertension through translational genetic and clinical observational studies. Hypertensive patients exhibit elevated ATP levels in their plasma compared with their normotensive counterparts, leading to enhanced T-cell responses in a P2X7-dependent manner. These T cells, specifically activated and effector memory T-cell subsets, are believed to contribute to immune activation in hypertension. Most importantly, the inactivation of P2RX7, a gene encoding a P2X7 receptor, attenuated angiotensin II-induced SBP increase and the dysfunction and remodelling of the mesenteric artery. Interestingly, the absence of P2RX7 resulted in an exaggeration of AngII-induced cardiac dysfunction and remodelling. However, when treated with a P2X7 antagonist, mice infused with AngII showed a decrease in blood pressure, an improvement in mesenteric artery function, and a reduction in perivascular infiltration of activated T cells and TEM cells, without any detrimental effects on cardiac function and remodelling. This discrepancy between genetic and pharmacological inhibition is interesting and requires further understanding. Additionally, the authors expand available evidence linking P2RX7 genetics with hypertension. Three single nucleotide polymorphisms in the P2RX7 gene increase the likelihood of DBP elevation, underscoring the potential genetic link to hypertension. Therefore, the current article strongly supports the concept that targeting P2X7 may be an effective strategy for managing hypertension and the associated vascular damage by moderating immune activation. Although this study supports the potential use of P2X7 antagonists in treating cardiovascular diseases by reducing inflammation [11], previous clinical findings in rheumatoid arthritis (RA) imply that we still need to better understand the mechanisms behind P2X7-mediated inflammation before we can embark on its targeting in cardiovascular conditions. P2X7's role in mediating arthritis is well documented in animal studies and in human type B synoviocytes from arthritic joints [12]. Synovial inflammation and radiographical damage are dose-dependently reduced upon P2X7 receptor antagonism, although systemic acute-phase response remains unaffected [13]. Similarly P2X7 and NLRP3 upregulation was observed in the kidneys of an experimental systemic lupus erythematosus (SLE) mouse model, and P2X7 blockade led to decreased lupus nephritis activity by inhibiting the NLRP3/ASC/caspase 1 pathway [14], although other studies propose a surprising protective P2X7 role in T-cell homeostasis and SLE development [15]. Human studies present a varied picture, with SLE patients’ peripheral blood mononuclear cells showing reduced P2X7 expression and increased NLRP3 expression compared with healthy controls [16]. Still, positive correlations were found between SLE disease activity index scores and Th17 cell P2X7 expression. Despite promising results in animal models, P2X7 receptor antagonists’ effectiveness has not translated into significant clinical outcomes. The P2X7 purinergic receptor antagonist AZD9056 did not show a significant effect in treating RA relative to placebo, with no effect on acute-phase reactants [17]. Similarly, another P2X7 receptor antagonist was ineffective compared with placebo for RA treatment [18]. The reason for this discrepancy remains unclear, but high diversity of P2X7 function due to P2X7 isoforms has been suggested along with possible divergent roles of the receptor at different stages of disease and in relation to heterogenous disease phenotypes. Importantly, however, these data indicate that P2X7 inhibition's efficacy may vary depending on the inflammatory disease type. Thus, it is important to emphasize that existing studies have not fully explored the role of P2X7 in cardiovascular injury, T-cell activation, and memory T-cell development in hypertension. As such, there is a need for further investigation into these areas, particularly in relation to how the P2X7 pathway might offer novel, precision-driven therapeutic opportunities for the management of hypertension and other cardiovascular conditions [2,19]. ACKNOWLEDGEMENTS T.J.G. is funded by the European Research Council (ERC and InflammaTENSION; ERC-CoG-726318), British Heart Foundation (FS/14/49/30838, RE/18/5/34216 and FS/4yPhD/F/20/34127A), European Commission and the National Centre for Research and Development (NCBR; Poland) (ERA-CVD/Gut-brain/8/2021; ERACVD/JTC2020/25/ImmuneHyperCog/2022). Conflicts of interest There are no conflicts of interest.