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

被引:7
作者
Raggi, Francesco [1 ]
Rossi, Chiara [1 ]
Faita, Francesco [2 ]
Distaso, Mariarosaria [1 ]
Kusmic, Claudia [2 ]
Solini, Anna [1 ]
机构
[1] Univ Pisa, Dept Surg Med Mol & Crit Area Pathol, Via Roma 67, I-56126 Pisa, Italy
[2] Italian Natl Res Council, Inst Clin Physiol, Pisa, Italy
关键词
low-grade inflammation; high fat diet; diastolic dysfunction; DIASTOLIC DYSFUNCTION; EXPRESSION; FIBROSIS; INJURY; IDENTIFICATION; ACTIVATION; MICRORNAS; PREVENTS; GANGLIA; MIR-126;
D O I
10.2147/JIR.S356038
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Purpose: 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, TNF alpha), 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-1 beta 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.
引用
收藏
页码:2425 / 2439
页数:15
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