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.

• Authors: Camila Guerra Martinez, Daniel Zamith-Miranda, Marcia Gracindo da Silva, Karla Consort Ribeiro, Izaíra Trincani Brandão, Celio Lopes Silva, Bruno Lourenço Diaz, Maria Bellio, Pedro Muanis Persechini, Eleonora Kurtenbach
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 16940 (Nov 23 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26592184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Autoantigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Il2ra protein, mouse
• Interleukin-17
• Interleukin-1beta
• Interleukin-2 Receptor alpha Subunit
• Receptor, Muscarinic M2
• Receptors, Purinergic P2X7
• Interferon-gamma

Topics

• Animals
• Autoantibodies (biosynthesis)
• Autoantigens (genetics, immunology)
• Cardiomyopathy, Dilated (genetics, immunology, pathology)
• Female
• Forkhead Transcription Factors (genetics, immunology)
• Gene Expression Regulation
• Heart Rate
• Immunization
• Interferon-gamma (biosynthesis, immunology)
• Interleukin-17 (biosynthesis, immunology)
• Interleukin-1beta (biosynthesis, immunology)
• Interleukin-2 Receptor alpha Subunit (genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (immunology, pathology)
• Physical Conditioning, Animal
• Plasmids (administration & dosage)
• Receptor, Muscarinic M2 (genetics, immunology)
• Receptors, Purinergic P2X7 (deficiency, genetics)
• Signal Transduction
• Spleen (immunology, pathology)
• T-Lymphocytes, Regulatory (immunology, pathology)
• Ventricular Remodeling