Extracellular ATP-P2X7-NLRP3 axis drives chronic heart failure progression, targeted by P2X7 antagonism and MCC950.

Persistent sterile inflammation significantly contributes to the progression of hypertension-induced chronic heart failure (CHF), a major cause of morbidity and mortality. Current standard-of-care often falls short in fully addressing the underlying inflammatory drivers. While the NLRP3 inflammasome is known to play a role in cardiac inflammation, the specific upstream mechanisms linking mechanical stress from pressure overload to its activation across different disease stages remain poorly understood. Characterizing this ATP-P2X7-NLRP3 axis could reveal novel, stage-specific therapeutic targets.

Researchers established a transverse aortic constriction (TAC) mouse model to induce pressure overload-induced chronic heart failure (CHF), following the animals longitudinally. Hemodynamic assessment and echocardiography were used to track cardiac function and remodeling. The study evaluated extracellular ATP signaling, P2X7 receptor activation, NLRP3 inflammasome priming and assembly, and downstream effector responses across various disease stages. Causality was rigorously tested using pharmacologic inhibition with P2X7 antagonism and the NLRP3 inhibitor MCC950, alongside genetic deletion of the Nlrp3 gene.

Pressure overload in the TAC mouse model induced a stage-dependent amplification of extracellular ATP-P2X7 signaling, which was consistently accompanied by progressive activation of NLRP3 inflammasome pathways throughout the disease course. These molecular changes were strongly associated with adverse cardiac remodeling, including significant macrophage accumulation and worsening fibrosis, ultimately leading to a decline in overall cardiac function. The study demonstrated a clear causal link:

Pharmacologic disruption of the ATP-P2X7 axis using P2X7 antagonism or the NLRP3 inhibitor MCC950, as well as genetic deletion of Nlrp3, consistently attenuated inflammasome signaling. This intervention significantly reduced adverse cardiac remodeling and notably improved both cardiac structure and function, highlighting the axis's critical role in CHF progression.