Abstract
Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) “young” and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process.
Highlights
The syndromes of accelerated aging have been proposed as models to simplify the analysis of the aging process, by restricting the focus to a more definable area [1]
In order to investigate on the roles of endothelial cells (ECs) senescence in Fabry disease (FD), we evaluated the effects of Gb-3 and Lyso-Gb3, the most abundant substances accumulated in FD patients, into the cells and in extracellular space, respectively
DiIsncuthssisiownork we explored the hypothesis that FD is a pathology associated with premIantuthreis awgoinrkg wsuecehxpalos rcehdrtohneichykpiodtnheeysisdtihseaat sFeDainsda pcahtrhoonliocgyobasstsroucciatitveed wpuitlhmporneamraydtuisreeaasgein[5g2]s.uBcheyaosncdhrtohneicevkiiddennecyedtihsaetasFeDanisdacshsroocniaicteodbwstrituhctaivseigpnuilfmicaonntalryyrdeidsueacesed[l5i2fe]. eBxepyeocntadntchyecoevmidpeanrecde ttohattheFDgeinsearasslopcoiaptueldatwiointh, oathseigr ndiafitcaasnutlpyproerdt uthceedlinlikfebeextwpeecetnanFcDy acnodmapgairnegd. tRoetcheentgsetnuedriaelspdoepmuolantsiotrna,teodthtehreddaytasrseugpuplaotriot nthoeflsinokmbeeatgwineegnhFaDllmaanrdksa,gliinkge. telomere attrition and DNA damage in FD patients or in experimental models [53]
Summary
The syndromes of accelerated aging have been proposed as models to simplify the analysis of the aging process, by restricting the focus to a more definable area [1]. Dysregulation of some aging hallmarks, such as telomere attrition and DNA damage, has been observed in FD patients, as compared to age-matched controls [10]. These data suggest that FD may be another disease associated with premature aging [11]. Senescence plays a physiological role in development and maintenance of tissue homeostasis, this process is a stress response triggered by insults associated with aging, such as oxidative stress, glycation, telomere shortening, side reactions, mutations, and aggregation of proteins [13]. Several recent evidences demonstrate that senescent cells are a source of circulating microRNAs (miRNAs) [14]
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