P2 X 7 receptor deficiency ameliorates high-fat-induced cardiac remodeling by improving oxidative stress through PI3K/AKT/GSK3β-mediated regulation of Nrf2.

Abnormal or excessive fat accumulation may lead to the development of cardiac remodeling. Yet, the mechanism of action remains unclear. We recently found that suppressing the P2 × 7 receptor (P2 × 7R) may alleviate high-fat (HF)-induced myocardial remodeling in mice. In this study, we further examined whether P2 × 7R affects oxidative stress, mainly nuclear factor E2-related factor 2 (Nrf2), in HF-induced cardiac remodeling. For in vivo testing, C57BL/6J wild-type mice and P2 × 7R−/− mice were given an HF diet or a standard diet (SD) for 24 weeks. For in vitro experiments, H9c2 cells were transfected with small-interfering RNA targeting P2 × 7R (si-P2 × 7R) or si-NC (Control), then treated with palmitic acid and a PI3K inhibitor. Echocardiograms were used to assess cardiac function post-modeling in mice. Immunohistochemistry, RT-PCR, and Western blot assessed mRNA and protein expression in cells and hearts. The TUNEL assay was used to evaluate cell death. P2 × 7R increased in heart tissues and H9c2 cells after stimulation by HF diet and PA, respectively. Moreover, P2 × 7R deficiency alleviated HF-induced pathological cardiac remodeling by improving the E’/A’ and E/A ratios, left ventricular ejection fraction (EF), and fractional shortening, and by decreasing inflammation, apoptosis, and oxidative stress induced by the HF diet. Mechanistically, we found that P2 × 7R can modulate Nrf2 activity via the PI3K/AKT/GSK3β signaling pathway. P2 × 7 receptor deficiency ameliorates cardiac remodeling induced by abnormal or excessive fat accumulation, reducing oxidative stress via PI3K/AKT/GSK3β-mediated regulation of Nrf2. P2 × 7R may serve as a new drug target for treating cardiac remodeling in obesity.Clinical trial number: Not applicable.