Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition

International Journal of Molecular Sciences

Andrea Lenzi¹  Valeria Riccieri²  Clara Crescioli³  Cristina Antinozzi³  Luigi di Luigi³  Francesco Marampon³  Rebecca L. Ross⁴  Giuseppina Abignano⁴  Francesco Del Galdo⁴  Clarissa Corinaldesi⁴  Maya H Buch⁴ 

[1] Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy;Department of Internal medicine and Medical Specialties, University Sapienza, 00185 Rome, Italy;Department of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, Italy;Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK;

关键词: CXCL10;    sildenafil;    systemic sclerosis;    myocytes;    inflammation;   

DOI  :  10.3390/ijms22062894

来源: DOAJ

【 摘 要 】

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. In vitro, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.

【 授权许可】

Unknown