Systemic sclerosis (SSc) is an immune disorder characterized by diffuse fibrosis and vascular abnormalities of the affected organs. Although the etiopathology of this disease is largely unknown, endothelial damage and oxidative stress appear implicated in its initiation and maintenance. Here, we show for the first time that circulating factors present in SSc sera increased reactive oxygen species (ROS) production, collagen synthesis, and proliferation of human pulmonary microvascular endothelial cells (HPMECs). The observed phenomena were also associated with endothelial to mesenchymal transition (EndMT) as indicated by decreased von Willebrand factor (vWF) expression and increased alpha-smooth muscle actin, respectively, an endothelial and mesenchymal marker. SSc-induced fibroproliferative effects were prevented by HPMECs exposition to the NADPH oxidase inhibitor diphenyleneiodonium, demonstrating ROS's causative role and suggesting their cellular origin. Sera from SSc patients showed significant changes in the expression of a set of fibrosis/EndMT-associated microRNAs (miRNA), including miR-21, miR-92a, miR-24, miR-27b, miR-125b, miR-29c, and miR-181b, which resulted significantly upregulated as compared to healthy donors sera. However, miR29b resulted downregulated in SSc sera, whereas no significant differences were found in the expression of miR-29a in the two experimental groups of samples. Taking together our data indicate NADPH oxidase-induced EndMT as a potential mechanism of SSc-associated fibrosis, suggesting fibrosis-associated miRNAs as potentially responsible for initiating and sustaining the vascular alterations observed in this pathological condition.

NADPH-derived ROS generation drives fibrosis and endothelial-to-mesenchymal transition in systemic sclerosis: Potential cross talk with circulating miRNAs / Posadino, A. M.; Erre, G. L.; Cossu, A.; Emanueli, C.; Eid, A. H.; Zinellu, A.; Pintus, G.; Giordo, R.. - In: BIOMOLECULAR CONCEPTS. - ISSN 1868-5021. - 13:1(2022), pp. 11-24. [10.1515/bmc-2021-0023]

NADPH-derived ROS generation drives fibrosis and endothelial-to-mesenchymal transition in systemic sclerosis: Potential cross talk with circulating miRNAs

Posadino A. M.;Erre G. L.;Emanueli C.;Zinellu A.;Pintus G.;Giordo R.
2022

Abstract

Systemic sclerosis (SSc) is an immune disorder characterized by diffuse fibrosis and vascular abnormalities of the affected organs. Although the etiopathology of this disease is largely unknown, endothelial damage and oxidative stress appear implicated in its initiation and maintenance. Here, we show for the first time that circulating factors present in SSc sera increased reactive oxygen species (ROS) production, collagen synthesis, and proliferation of human pulmonary microvascular endothelial cells (HPMECs). The observed phenomena were also associated with endothelial to mesenchymal transition (EndMT) as indicated by decreased von Willebrand factor (vWF) expression and increased alpha-smooth muscle actin, respectively, an endothelial and mesenchymal marker. SSc-induced fibroproliferative effects were prevented by HPMECs exposition to the NADPH oxidase inhibitor diphenyleneiodonium, demonstrating ROS's causative role and suggesting their cellular origin. Sera from SSc patients showed significant changes in the expression of a set of fibrosis/EndMT-associated microRNAs (miRNA), including miR-21, miR-92a, miR-24, miR-27b, miR-125b, miR-29c, and miR-181b, which resulted significantly upregulated as compared to healthy donors sera. However, miR29b resulted downregulated in SSc sera, whereas no significant differences were found in the expression of miR-29a in the two experimental groups of samples. Taking together our data indicate NADPH oxidase-induced EndMT as a potential mechanism of SSc-associated fibrosis, suggesting fibrosis-associated miRNAs as potentially responsible for initiating and sustaining the vascular alterations observed in this pathological condition.
NADPH-derived ROS generation drives fibrosis and endothelial-to-mesenchymal transition in systemic sclerosis: Potential cross talk with circulating miRNAs / Posadino, A. M.; Erre, G. L.; Cossu, A.; Emanueli, C.; Eid, A. H.; Zinellu, A.; Pintus, G.; Giordo, R.. - In: BIOMOLECULAR CONCEPTS. - ISSN 1868-5021. - 13:1(2022), pp. 11-24. [10.1515/bmc-2021-0023]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/283934
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