P2X7 Receptor and Heart Function in a Mouse Model of Systemic Inflammation Due to High Fat Diet

Francesco Raggi,1 Chiara Rossi,1 Francesco Faita,2 Mariarosaria Distaso,1 Claudia Kusmic,2 Anna Solini1 1Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy; 2Institute of Clinical Physiology, Italian National Research Council, Pisa, ItalyCorrespondence: Anna Solini; Francesco Raggi, Department of Surgical Medical Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, Pisa, I-56126, Italy, Tel +39-50-993482 ; +39-50-992861, Fax +39-50-553235, Email anna.solini@med.unipi.it; francesco.raggi@unipi.itPurpose: Low-grade inflammation contributes to heart failure in obesity or type 2 diabetes mellitus. The P2X7 receptor (P2X7R) is a key regulator of several pro-inflammatory responses in multiple tissues and organs; however, its involvement in the onset of heart dysfunction remains unclear. The study evaluated the role of P2X7R as a cardiac function regulator in C57BL/6J wild-type (WT) and P2X7R knockout (KO) mice by inducing systemic inflammation with high fat diet (HFD).Methods: Specific parameters of systolic and diastolic function and heart morphology were measured in vivo before animal sacrifice by high-frequency ultrasonographic analysis. Gene and protein expression of cardiac biomarkers associated with inflammatory-oxidative pathways were evaluated by real-time PCR and Western Blotting.Results: P2X7R-mediated up-regulation of the NLRP3-caspase-1 complex, increased expression of key oxidative stress (NOS-2, TNFα), and chemotactic (MCP-1) mediators were revealed in WT-HFD animals. In KO-HFD mice, such inflammatory-oxidative pathway was silent. Nevertheless, HFD induced in vivo a clear alteration of diastolic pattern (E/A: p < 0.03 vs WT-HFD) and a cardiac morphologic remodelling (left ventricular mass: p < 0.05 vs WT-HFD) only in P2X7R KO animals. Surprisingly, the transcriptional and protein expression of IL-1β and IL-6, usually regulated through P2X7R activation, were significantly higher in KO-HFD than in WT-HFD mice (both p < 0.05). Furthermore, an up-regulation of miR-214 and a down-regulation of miR-126 in heart of HFD-KO mice were observed, suggesting a link between such epigenetic dysregulation and cytokine overexpression as a potential pathophysiologic mechanism concurring to the progressive cardiac dysfunction.Conclusion: These findings seem to suggest a cardioprotective role of P2X7R toward this tissue-specific inflammatory damage, likely through tissue homeostasis and organ functionality preservation.Keywords: low-grade inflammation, high fat diet, diastolic dysfunction, P2X7 receptor