Cargando…

Citrullination is linked to reduced Ca(2+) sensitivity in hearts of a murine model of rheumatoid arthritis

AIMS: Cardiac contractile dysfunction is prevalent in rheumatoid arthritis (RA), with an increased risk for heart failure. A hallmark of RA has increased levels of peptidyl arginine deaminases (PAD) that convert arginine to citrulline leading to ubiquitous citrullination, including in the heart. We...

Descripción completa

Detalles Bibliográficos
Autores principales: Pironti, Gianluigi, Gastaldello, Stefano, Rassier, Dilson E., Lanner, Johanna T., Carlström, Mattias, Lund, Lars H., Westerblad, Håkan, Yamada, Takashi, Andersson, Daniel C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788013/
https://www.ncbi.nlm.nih.gov/pubmed/36002394
http://dx.doi.org/10.1111/apha.13869
Descripción
Sumario:AIMS: Cardiac contractile dysfunction is prevalent in rheumatoid arthritis (RA), with an increased risk for heart failure. A hallmark of RA has increased levels of peptidyl arginine deaminases (PAD) that convert arginine to citrulline leading to ubiquitous citrullination, including in the heart. We aimed to investigate whether PAD‐dependent citrullination in the heart was linked to contractile function in a mouse model of RA during the acute inflammatory phase. METHODS: We used hearts from the collagen‐induced arthritis (CIA) mice, with overt arthritis, and control mice to analyze cardiomyocyte Ca(2+) handling and fractional shortening, the force‐Ca(2+) relationship in isolated myofibrils, the levels of PAD, protein post‐translational modifications, and Ca(2+) handling protein. Then, we used an in vitro model to investigate the role of TNF‐α in the PAD‐mediated citrullination of proteins in cardiomyocytes. RESULTS: Cardiomyocytes from CIA mice displayed larger Ca(2+) transients than controls, whereas cell shortening was similar in the two groups. Myofibrils from CIA hearts required higher [Ca(2+)] to reach 50% of maximum shortening, ie Ca(2+) sensitivity was lower. This was associated with increased PAD2 expression and α‐actin citrullination. TNF‐α increased PAD‐mediated citrullination which was blocked by pre‐treatment with the PAD inhibitor 2‐chloroacetamide. CONCLUSION: Using a mouse RA model we found evidence of impaired cardiac contractile function linked to reduced Ca(2+) sensitivity, increased expression of PAD2, and citrullination of α‐actin, which was triggered by TNF‐α. This provides molecular and physiological evidence for acquired cardiomyopathy and a potential mechanism for RA‐associated heart failure.