The novel P2X7 receptor antagonist PKT100 improves cardiac function and survival in pulmonary hypertension by direct targeting of the right ventricle

Abstract

<jats:p> This study demonstrates the therapeutic potential for right-sided heart failure of a novel inhibitor of the P2X7 receptor (P2X7R). Inflammatory signaling and right ventricular function were improved in a mouse model of pulmonary fibrosis with secondary pulmonary hypertension when treated with this inhibitor. Importantly, survival was also improved, suggesting that this inhibitor, and other P2X7R antagonists, could be uniquely effective in right ventricle (RV)-targeted therapy in pulmonary hypertension. This addresses a major limitation of current treatment options, where the significant improvements in pulmonary pressures ultimately do not prevent mortality due to RV failure. </jats:p>

Purinoceptor: a novel target for hypertension

“…In the animal models with PAH, inhibition of P2X7R attenuated the inflammation [147,148], pulmonary arteries remodelling [147,149], and right ventricular function [147,148]. The blockade effect of P2X7R on PAH and RV complications differed from current treatment options, where the significant improvements in pulmonary pressures ultimately do not prevent mortality due to RV failure [148]. Blockade of P2Y1R also decreased pulmonary arterial pressure in swine with acute hypoxia-induced pulmonary hypertension [150].…”

P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

“…In another study using the same model, Brilliant Blue G (BBG), a P2X7 receptor antagonist, not only alleviated the remodeling of pulmonary vessels and function but also reduced the levels of pro-inflammatory cytokine IL-1β and tumor necrosis factor α through the P38/MAPK signaling pathway ( Duan et al, 2018 ). Interestingly, a novel inhibitor of P2X7 receptor PKT100 improved the right ventricle (RV) contractility and systolic function and survival in the PAH mice model induced by bleomycin, with no effect on pulmonary arterial pressure and pulmonary vascular remodeling ( Hansen et al, 2020 ). This provides a new perspective for current treatment strategies that target both the RV function and pulmonary vessels, which may improve the prognosis of PAH patients.…”

“…Recent studies demonstrated that purinergic P2X7 receptors played an important role in a variety of cardiovascular diseases, including atherosclerosis ( Piscopiello et al, 2013 ; Wernly and Zhou, 2020 ), arrhythmia after myocardial infarction ( Gao et al, 2017 ), vascular remodeling ( Mahdi et al, 2018 ; Hansen et al, 2020 ), and cardiac fibrosis ( Zhou J. et al, 2020 ). P2X7 receptors are highly expressed in immune cells, including dendritic cells, mast cells, macrophages, and monocytes.…”

Innovative Anti-Inflammatory and Pro-resolving Strategies for Pulmonary Hypertension: High Blood Pressure Research Council of Australia Award 2019

“…33 Duan et al 68 similarly implicated the P2X7 receptor in ischemia reperfusion lung injury in PH rats. A more recent study conducted by Hansen et al 34 revealed that a highly selective allosteric antagonist of the P2X7 receptor, PKT100, prevents RVH, normalizes selected echocardiographic markers of RV function, and improves survival in bleomycin-induced PF with secondary PH in mice. Importantly, these actions occurred independently of an effect on RVSP, pulmonary vascular remodeling, or PF.…”

“…Numerous animal studies have affirmed the notion that NLRP3 inflammasome signaling may offer several Ellagic acid prevents MCT-induced PH 27 SOD-mimetic attenuates hypoxia-induced PH 28 SOD2 −/+ mice display exacerbated CIH-induced PH 29,30 Uric acid Hyperuricemia in PH patients correlates with severity and prognosis 31,32 ATP/P2X7R P2X7R inhibition improves PH 33 PKT100 (allosteric antagonist) prevents RVH 34 Subunits ASC ASC −/− mice are protected from hypoxia-induced PH 35 Caspase-1 Caspase-1 −/− mice are protected from hypoxia-induced PH 36 Caspase-1 inhibitors Ac-YVAD-cmk and VX-765 prevent and reverse rat hypoxia-and MCT-induced PH 37 Cytokines IL-1β Inhibition improves PH 38,39 Increased levels in PH patients 40,41 IL-1Ra protects newborn mice from BPD-PH 42 Anakinra ↓ hsCRP and ↓ HF symptoms, trend ↓ IL-6 in PH patients 43 Tet2 −/− mice develop spontaneous PH which is reversed by anti-IL-1β antibody 44 Tet2 mutations associated with PH, ↑ IL-1β (IL-6 and IL-12) levels 44 IL-18 IL-18 −/− mice are protected from hypoxia-induced PH 45 Increased circulating levels in patients 46 IL-18BP treatment protects mice from hypoxia-induced PH 47 ASC indicates apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD); BPD, bronchopulmonary dysplasia; CIH, chronic intermittent hypoxia; HF, heart failure; hsCRP, high-sensitivity C reactive protein; IL, interleukin; IL-18BP, IL-18 binding protein; IL-1Ra, IL-1 receptor antagonist; MCT, monocrotaline; Nrf2, nuclear factor erythroid 2-related factor 2; P2X7R, P2X purinoceptor 7; PH, pulmonary hypertension; ROS, reactive oxygen species; RVH, right ventricular hypertrophy; SOD, superoxide dismutase; SuHx, SU5416/hypoxia; and Tet2, ten-eleven translocation methylcytosine dioxygenase 2. potential targets for pharmacotherapy in PH. Indeed, ROS are thought to be activators of the NLRP3 inflammasome (Figure 1) 18,52,58 and Kang et al 26 found that sulforaphane, an activator of antioxidant signaling pathways downstream of Nrf2 (nuclear factor erythroid 2-related factor 2), was able to prevent the development of SU5416 (sugen)/hypoxia-induced PH in mice, with a concurrent reduction in lung and cardiac NLRP3 expression.…”