Dataset Information

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

ABSTRACT: Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

SUBMITTER: Barinda AJ

PROVIDER: S-EPMC6981212 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Barinda Agian Jeffilano AJ Ikeda Koji K Nugroho Dhite Bayu DB Wardhana Donytra Arby DA Sasaki Naoto N Honda Sakiko S Urata Ryota R Matoba Satoaki S Hirata Ken-Ichi KI Emoto Noriaki N

Nature communications 20200124 1

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaire ...[more]

PMID: 31980643

Similar Datasets

Project description:BACKGROUND:Disturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of TERF2IP S205 and subsequent nuclear export of the TERF2IP-TERF2 complex. In this study, we investigated TERF2IP-dependent gene expression and its role in regulating d-flow-induced SASP. METHODS:A principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by TERF2IP in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-?B activation and the expression of adhesion molecules. The involvement of TERF2IP S205 phosphorylation in d-flow-induced SASP was assessed by depletion of TERF2IP and mutation of the phosphorylation site. RESULTS:Our unbiased transcriptome analysis showed that TERF2IP caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of TERF2IP and overexpression of the TERF2IP S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-?B activation in ECs via suppression of p53, p21, and telomerase (TERT) induction. CONCLUSIONS:MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.

Project description:BackgroundFat grafting has been regarded as a promising approach for regenerative therapy. Given the rapidly aging population, better understanding of the effect of age on fat graft outcomes and the underlying mechanisms is urgently needed.MethodsC57/BL6 mice [old (O, 18-20-month-old) and young (Y, 4-month-old)] were randomized to four fat graft groups [old-to-old (O-O), young-to-young (Y-Y), old-to-young (O-Y), and young-to-old (Y-O)]. Detailed cellular events before and after grafting were investigated by histological staining, RNA sequencing, and real-time polymerase chain reaction. The adipogenic differentiation potential of adipose-derived mesenchymal stem cells (AD-MSCs) from old or young donors was investigated in vitro. Additionally, adipogenesis of AD-MSCs derived from old recipients was evaluated in the culture supernatant of old or young donor fat tissue.ResultsAfter 12 weeks, the volume of fat grafts did not significantly differ between the O-O and O-Y groups or between the Y-Y and Y-O groups, but was significantly smaller in the O-O group than in the Y-O group and in the O-Y group than in the Y-Y group. Compared with fat tissue from young mice, senescence-associated secretory phenotype (SASP) factors were upregulated in fat tissue from old mice. Compared with the Y-O group, adipogenesis markers were downregulated in the O-O group, while SASP factors including interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were upregulated. In vitro, AD-MSCs from old donors showed impaired adipogenesis compared with AD-MSCs from young donors. Additionally, compared with the culture supernatant of young donor fat tissue, the culture supernatant of old donor fat tissue significantly decreased adipogenesis of AD-MSCs derived from old recipients, which might be attributable to increased levels of SASP factors.ConclusionsAge has detrimental effects on fat graft outcomes by suppressing adipogenesis of AD-MSCs and upregulating expression of SASP factors, and fat graft outcomes are more dependent on donor age than on recipient age. Thus, rejuvenating fat grafts from old donors or banking younger adipose tissue for later use may be potential approaches to improve fat graft outcomes in older adults.

Project description:Endothelial dysfunction, impaired angiogenesis and cellular senescence in type 2 diabetes constitute dominant risk factors for chronic non-healing wounds and other cardiovascular disorders. Studying these phenomena in the context of diabetes and the TSP1-CD-47 signaling dictated the use of the in vitro wound endothelial cultured system and an in vivo PVA sponge model of angiogenesis. Herein we report that diabetes impaired the in vivo sponge angiogenic capacity by decreasing cell proliferation, fibrovascular invasion and capillary density. In contrast, a heightened state of oxidative stress and elevated expression of TSP1 and CD47 both at the mRNA and protein levels were evident in this diabetic sponge model of wound healing. An in vitro culturing system involving wound endothelial cells confirmed the increase in ROS generation and the up-regulation of TSP1-CD47 signaling as a function of diabetes. We also provided evidence that diabetic wound endothelial cells (W-ECs) exhibited a characteristic feature that is consistent with cellular senescence. Indeed, enhanced SA-?-gal activity, cell cycle arrest, increased cell cycle inhibitors (CKIs) p53, p21 and p16 and decreased cell cycle promoters including Cyclin D1 and CDK4/6 were all demonstrated in these cells. The functional consequence of this cascade of events was illustrated by a marked reduction in diabetic endothelial cell proliferation, migration and tube formation. A genetic-based strategy in diabetic W-ECs using CD47 siRNA significantly ameliorated in these cells the excessiveness in oxidative stress, attenuation in angiogenic potential and more importantly the inhibition in cell cycle progression and its companion cellular senescence. To this end, the current data provide evidence linking the overexpression of TSP1-CD47 signaling in diabetes to a number of parameters associated with endothelial dysfunction including impaired angiogenesis, cellular senescence and a heightened state of oxidative stress. Moreover, it may also point to TSP1-CD47 as a potential therapeutic target in the treatment of the aforementioned pathologies.

Dataset Information

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Publications

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets