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

Abstract

Autoantibodies against the M2 receptors (M2AChR) 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 M2AChR cDNA sequence, WT mice produced anti-M2AChR 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 M2AChR 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. M2AChR 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.

Purinergic Signaling in the Cardiovascular System

“…Disruption of ATP synthase has been reported to contribute to diabetic cardiomyopathy. 141 Roles for P2X7 receptors in dilated cardiomyopathy have been reported 142 and also for K ATP channels. 143 P2Y 11 receptor agonists may be a means to reduce cardiac fibrosis.…”

P2X7 receptor in cardiovascular disease: The heart side

“…Surprisingly, despite having a lower immune response, the P2X7 −/− mice developed features of dilated cardiomyopathy. The results indicate that dilated cardiomyopathy phenotype was not associated with immunological changes induced by P2X7 itself, but most likely due to the unique alterations on heart's electrocardiogram patterns on P2X7 −/− mice, which was aggravated by anti‐M 2 AChR antibodies titres . Finally, the patient's heart biopsy and post‐mortem samples revealed the occurrence of inflammasome assembly after acute myocarditis, while in mice, a similar phenotype was observed at hypertrophic hearts, reinforcing the relevance of this inflammatory process in cardiac injury.…”

“…itself, but most likely due to the unique alterations on heart's electrocardiogram patterns on P2X7 −/− mice, which was aggravated by anti-M 2 AChR antibodies titres. 151 Finally, the patient's heart biopsy and post-mortem samples revealed the occurrence of inflammasome assembly after acute myocarditis, 152 while in mice, a similar phenotype was observed at hypertrophic hearts, 153 reinforcing the relevance of this inflammatory process in cardiac injury.…”

“…Although the use of a cardiac diseases–animal model with the P2X7 receptor antagonist oxATP (1 mg/kg/day) or BBG (30 mg/kg) did not cause major alterations on the electrocardiogram, the ST segment did not present the same pattern in comparison to untreated animals . Segment ST alteration was also observed in P2X7 −/− knockout female mice, which was aggravated by aging . Electrocardiographic alterations are normally associated with the change in the action potential (phase 1) followed by a change in the cell‐to‐cell electrical coupling (phase 2).…”

“…148 Segment ST alteration was also observed in P2X7 −/− knockout female mice, which was aggravated by aging. 151 Electrocardiographic alterations are normally associated with the change in the action potential (phase 1) followed by a change in the cell-to-cell electrical coupling (phase 2).…”