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Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation

ABSTRACT: Vascular dysfunction is one of the typical characteristics of aging, but its contributing roles to systemic aging and the therapeutic potential is lacking experimental evidence. Accumulating data suggest that the mechanisms underlying aging are similar to those governing Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disease, in which affected patients succumb to cardiovascular diseases (CVDs). Here, we generated a knock-in mouse model with the causative HGPS LmnaG609G mutation, called progerin. We crossed Lmnaf/f mice with a Tie2-Cre line to get Lmnaf/f;TC mice, which exhibit defective microvasculature and neovascularization, accelerated aging and shortened lifespan. Single-cell transcriptomic analysis of murine lung endothelial cells (MLECs) revealed a significant upregulation of inflammatory response. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE138975 | GEO | 2019/10/17

REPOSITORIES: GEO

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Transcriptomic profiling of ZMPSTE24 knockout endothelial cells: implication of endothelial dysfunction in HGPS

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). The molecular basis underlying premature aging driven cardiovascular diseases remains incompletely understood. Since endothelial dysfunction is involved in the initiation and progression of cardiovascular diseases. We hypothesized that HGPS-causing progerin (a mutant form of lamin A) and farnesylated prelamin A drives endothelial dysfunction and cardiovascular disease. In our study, we performed transcriptomic profiling of ZMPSTE24-/- mouse endothelial cells, hoping to find the missing link between progeria and atherosclerosis. We observed that ZMPSTE24-/- endothelial cells have increased farnesylated prelamin A accumulation, and show nuclear structure abnormality. Analysis of RNA-seq data revealed that multiple endothelial homeostasis-related genes and pathways are altered by ZMPSTE24 deletion. Further studies are needed to characterize the biological functions of ZMPSTE24 in the pathogenesis of progeria-associated atherosclerosis.

2019-11-27 | GSE137501 | GEO

Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation

Project description:Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation

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SILAC pulse labeling in HGPS fibroblasts - HGPS samples

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Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease. Genome-wide transcriptional profiling was carried out to assess functional phenotypic changes in endothelial cells (EC) as a result of progerin expression. Cultured EC were infected with an adenovirus expressing progerin (Ad-Progerin), and as a control, an adenovirus that did not express any construct (Ad-Null). Experiments were preformed with three different EC cultures.

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Expression data from transformed WT and HGPS cell lines, including HGPS cells after knock-down of BRD4

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Expression data from transformed WT and HGPS cell lines, including HGPS cells after knock-down of BRD4

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The effect of progerin expression on alternative splicing in keratinocytes of HGPS mice

Project description:Exon level expression analysis for the HGPS pathological aging study data set to analyze the effect of progerin expression on alternative splicing in keratinocytes of HGPS mice. Analysis of the effect of pathological aging (transgenic progerin expression) on alternative splicing (AS) using exon microarrays to interrogate the differential exon usage of the entire genome of HGPS mice (postnatal day 24 and 35) and their wild-type litter mates. Our results suggests that early expression of progerin impairs developmental splicing but that as progerin accumulates, the number of genes with AS increases, similar to what is observed in aging wild-type mice. This dataset is one of the 2 datasets in the overall study. An additional data set series is available with exon expression analysis of aging wild-type mice to analyze the effect of age on alternative splicing during physiological aging. The two datasets are linked together in the SuperSeries GSE67289. A link to the SuperSeries is available at the bottom of this page. 16 skin keratinocyte samples from 2 different age groups: postnatal day 24 and postnatal day 35, from 8 HGPS samples and 8 genotype negative (wild-type) littermates.

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