Chagasic antibodies induce cardiac COX-2/iNOS mRNA expression with PGE2/NO production.
We demonstrate that serum IgG in chagasic patients interacting with the second extracellular loop of human cardiac M(2) muscarinic acetylcholine receptors (M(2) mAChR) trigger the production of PGE(2) and NO, that in turn induces COX-2/iNOS mRNA expression. An association between serum anti-M(2) peptide IgG, anti-cardiac membrane IgG and PGE(2) levels (p<0.05) in chagasic dysautonomic patients was observed. Thus, we establish that serum anti-mAChR autoantibodies and PGE(2) might be considered as early markers of Chagas' associated dysautonomia. Affinity purified anti-M(2) peptide IgG from chagasic sera, while stimulating myocardial M(2) mAChR, it exerts an increase on PGE(2) generation and NOS activity, as well as COX-2/iNOS isoforms mRNA expression. The expression of these genes is related with phosphoinositides (PIs), cGMP accumulation and PKC activity. Inhibition of these enzymes shows that chagasic autoantibodies up-regulation of COX-2/iNOS mRNA level is under the control of endogenous iNO/cGMP signaling system. These results provide a novel insight into the role that cholinoceptor antibodies play in the development of myocardial inflammation. To our knowledge, there has been no previous report showing that an antibody interacting with heart mAChR can act as expression inducer of proinflammatory mediators.
Ganzinelli
Sabrina
S
Pharmacology Unit, School of Dentistry, University of Buenos Aires and National Research Council (CONICET), Buenos Aires, Argentina.
Borda
Enri
E
Joensen
Lilian
L
Sterin-Borda
Leonor
L
D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood*; D016718:Arachidonic Acid / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D054969:Primary Dysautonomias / Q000276:immunology / Q000469:parasitology; D012333:RNA, Messenger / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000276:immunology / Q000378:metabolism
D000913:Antibodies, Protozoan; D001323:Autoantibodies; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; D016718:Arachidonic Acid; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone