P2X7R deficiency alleviates cardiac senescence by enhancing mitophagy via the HuR/TRIM26/NR4A1 axis

Ageing is a significant risk factor for pathophysiological alterations in the heart, but the intrinsic mechanisms by which these occur have yet to be fully elucidated. Purinergic 2×7 receptor (P2X7R) is important for the pathogenesis of numerous cardiovascular diseases; nevertheless, its function in the process of cardiac ageing remains uncertain.

This study utilised P2X7R knockout (P2X7R^-/^-) mice. An ageing model was established by either maintaining mice until they reached 20 months of age or performing chronic subcutaneous injection of D-galactose (D-gal). Recombinant adeno-associated virus serotype 9 (AAV9) was employed to achieve cardiac-specific overexpression of P2X7R and nuclear receptor subfamily 4 group A member 1 (NR4A1). Cardiac function and histopathological changes in cardiac tissues were evaluated. Transcriptome sequencing was further applied to elucidate the potential mechanisms of P2X7R in cardiac senescence.

Our result show that serum levels of P2X7R increase with advancing age in humans and that P2X7R expression is upregulated during cardiac senescence in mice. P2X7R deficiency alleviates ageing-related cardiac dysfunction, senescence phenotypes and impaired mitophagy. Cardiomyocyte-specific overexpression of P2X7R with AAV9 exacerbates the myocardial dysfunction, senescence phenotype and mitophagy disruption induced by D-gal. Mechanistically, P2X7R promotes human antigen R (HuR) nucleocytoplasmic shuttling in ageing hearts, thereby increasing the mRNA stability of tripartite motif containing 26 (TRIM26) and the expression of the E3 ubiquitin ligase TRIM26. TRIM26 subsequently mediates NR4A1 ubiquitination, leading to its proteasomal degradation, which subsequently suppresses mitophagy in cardiomyocytes and ultimately accelerates cardiac ageing.

Our findings provide valuable insights into the role of P2X7R in cardiac ageing and identify the HuR/TRIM26/NR4A1 axis as a key signalling pathway through which P2X7R regulates cardiac ageing.