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P2×7 purinergic signaling in dilated cardiomyopathy induced by auto-immunity against muscarinic M2 receptors: autoantibody levels, heart functionality and cytokine expression

2015; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/srep16940

2045-2322

Camila Guerra Martinez, Daniel Zamith‐Miranda, Marcia Gracindo da Silva, Karla Consort Ribeiro, Izaíra Trincani Brandão, Célio Lopes Silva, Bruno L. Diaz, Maria Bellio, Pedro M. Persechini, Eleonora Kurtenbach,

Immune Cell Function and Interaction

Abstract Autoantibodies against the M 2 receptors (M 2 AChR) have been associated with Dilated Cardiomyopathy (DCM). In the heart, P2×7 receptors influence electrical conduction, coronary circulation and response to ischemia. They can also trigger pro-inflammatory responses and the development of neurological, cardiac and renal disorders. Here, P2×7 −/− mice displayed an increased heart rate and ST segment depression, but similar exercise performance when compared to wild type (WT) animals. After immunization with plasmid containing M 2 AChR cDNA sequence, WT mice produced anti-M 2 AChR antibodies, while P2×7 −/− mice showed an attenuated production. Despite this, WT and P2×7 −/− showed left ventricle cavity enlargement and decreased exercise tolerance. Transfer of serum from M 2 AChR WT immunized mice to näive recipients led to an alteration in heart shape. P2×7 −/− mice displayed a significant increase in the frequency of spleen regulatory T cells population, which is mainly composed by the FoxP3 + CD25 − subset. M 2 AChR WT immunized mice showed an increase in IL-1β, IFNγ and IL-17 levels in the heart, while P2×7 −/− group produced lower amounts of IL-1β and IL-17 and higher amounts of IFNγ. These results pointed to previously unnoticed roles of P2×7 in cardiovascular and immune systems and underscored the participation of IL-17 and IFNγ in the progress of autoimmune DCM.