P2×7 purinergic signaling in dilated cardiomyopathy induced by auto-immunity against muscarinic M 2 receptors: Autoantibody levels, heart functionality and cytokine expression

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 3 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 3. These results pointed to previously unnoticed roles of P2×7 in cardiovascular and immune systems, and underscored the participation of IL-17 and IFNγ 3 in the progress of autoimmune DCM.