Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy
| Autor: | Christian Maasch, Axel Vater, Constantinos H. Davos, Yassemi Capetanaki, Aimilia Varela, Ioanna Kostavasili, Michalis Katsimpoulas, Nikolaos C. Athanasiadis, J. Peter van Tintelen, Stelios Psarras, Manolis Mavroidis |
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| Přispěvatelé: | Cardiovascular Centre (CVC), Amsterdam Cardiovascular Sciences, Human Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Pathology Physiology C5A RECEPTOR Cardiomyopathy Fluorescent Antibody Technique Arrhythmias C5a receptor DISEASE Desmin Mice REPERFUSION INJURY MUTATION Cytoskeleton Mice Knockout Innate immunity INFARCT SIZE Middle Aged Receptors Complement ANIMAL-MODELS HEART-FAILURE Female medicine.symptom Cardiomyopathies Cardiology and Cardiovascular Medicine Adult Cardiac function curve RIGHT-VENTRICULAR CARDIOMYOPATHY medicine.medical_specialty Blotting Western Complement C5a Inflammation Biology Physiology (medical) Genetic model In Situ Nick-End Labeling medicine Animals Humans DESMIN GENE SEPSIS Arrhythmias Cardiac medicine.disease Genetic models Complement system Disease Models Animal Myocardial inflammation Heart failure Reperfusion injury |
| Zdroj: | Basic Research in Cardiology, 110(27):27. SPRINGER HEIDELBERG Basic research in cardiology, 110(3). D. Steinkopff-Verlag |
| ISSN: | 0300-8428 |
| Popis: | Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (2-3 weeks of age), with consequently reduced myocardial remodeling and the absence of a direct long-lasting detrimental effect of C5a-C5aR signaling on cardiomyocytes, could explain the beneficial action of C5aR ablation in Des-/- cardiomyopathy. We extend the relevance of these findings to human pathophysiology by showing for the first time significant complement activation in the cardiac tissues of patients with ACM, thus suggesting that complement modulation could be a new therapeutic target for ACM. |
| Databáze: | OpenAIRE |
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