Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating expression levels were up-regulated in children with familial hypercholesterolaemia (FH). control cholesterol homoeostasis and recently has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the family. Our previous studies showed that the ROS-dependent up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating was induced in FH children, and whether a correlation existed with Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and levels were measured. We found that was up-regulated in FH compared with HS (4.00 ± 0.48-fold increase, <0.05) and exhibited a positive correlation with did not correlate with plasma lipids, but correlated with C-reactive protein (CRP) plasma levels and glycaemia (GLI). Ordinary least squares (OLS) regression analysis revealed that was significantly affected by GLI and by (<0.01; <0.001 respectively). Moreover, we found that overexpression, in different cell lines, decreased ZEB1 expression and up-regulated both the intracellular and the extracellular expression levels. In conclusion, circulating is up-regulated in FH, probably due to oxidative stress and inflammation and via a-ZEB1-dependent mechanism. The present study could provide the first evidence to point to the use of and, as early biomarkers of CVD, in paediatric FH.
Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc−/− muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc−/− fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.
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