Patient iPSCs identify vascular smooth muscle AADAC as protective against atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA454701 | ENA |
REPOSITORIES: ENA
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Project description:Cardiovascular disease (CVD) is the most common cause of death in patients with type II diabetes mellitus (T2DM). Although susceptibility to CVD is different for every patient, why some patients with T2DM develop CVD while others are protected has not yet been clarified. Patient-derived induced pluripotent stem cells (iPSCs) have been utilized to reveal the influence of genotype on phenotype and have the potential to connect a clinical phenotype to a causal gene. Using T2DM patient-derived iPSCs, we found that in patients protected from CVD there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC) in vascular smooth muscle cells (VSMCs). To investigate the function of AADAC in CVD, we overexpressed this esterase in human primary coronary artery VSMCs and VSMCs differentiated from iPSCs and observed that the number of lipid droplets per cell was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids such as triacylglycerol and diacylglycerol and an increase in membrane phospholipids suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration, proliferation, and apoptosis were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein (Apo) E knockout mice overexpressing VSMC-specific Aadac showed significant amelioration of atherosclerotic lesions. Isolated VSMCs from these mice also displayed decreased lipid droplets, storage lipids, cell migration, proliferation, and apoptosis, all of which were consistent with human data. Our findings suggest that elevated AADAC expression in VSMCs protects T2DM patients from CVD. This study also highlights the potential of patient-derived iPSCs to investigate disease associated phenotypes as a means of elaborating the molecular mechanisms underlying disease pathology.
2020-05-18 | GSE113969 | GEO
Project description:Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barths Syndrome, which is characterized by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs).
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Project description:We used microarrays to detail transcriptional changes in cultured human smooth muscle cells in response to acute and chronic 2-methoxyestradiol treatment 2-ME, an endogenous metabolite. of estradiol, not only exerts cytotoxic effects on cancer cells but it also protects against multiple proliferative disorders, including atherosclerosis and injury-induced intimal thickening Keywords: treatment vs. control Human aortic smooth muscle cells cultures with/without 2-methoxyestradiol (acute/chronic treatment)
2008-12-30 | E-GEOD-12261 | biostudies-arrayexpress
Project description:Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.
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Project description:This SuperSeries is composed of the following subset Series:; GSE13835: Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of C57Bl/6 mice at age of 4 months; GSE13836: Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of apoE-/- mice at age of 4 months Experiment Overall Design: Refer to individual Series
2009-05-27 | E-GEOD-13865 | biostudies-arrayexpress
Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC transdifferentiation into macrophage-like SMCs. Furthermore, during transdifferentiation, the SMCs' expression of PADI4 upregulating and SMC generated extracellular trap, a web-like structure, which plays key role in the development of atherosclerosis plaque. To reveal the function of SMC's generating ETs during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of mouse atherosclerotic plaques.
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Project description:We used microarrays to detail transcriptional changes in cultured human smooth muscle cells in response to acute and chronic 2-methoxyestradiol treatment 2-ME, an endogenous metabolite. of estradiol, not only exerts cytotoxic effects on cancer cells but it also protects against multiple proliferative disorders, including atherosclerosis and injury-induced intimal thickening Keywords: treatment vs. control
2008-12-31 | GSE12261 | GEO
Project description:Adventitial stem cells (ASCs), identified by Gli1 expression, have been proposed as key contributors to the vascular smooth muscle cell (SMC) population during atherosclerosis development. However, their precise role remains a subject of debate. To clarify this, we initially used a Gli1-CreER lineage tracing tool to track these cells in an atherosclerosis model. Our fate-mapping studies revealed that Gli1+ cells contribute to a small subset of SMCs. To definitively differentiate between the true lineage transformation and potential ectopic labeling by Gli1-CreER in SMCs, we developed a dual recombinase-mediated genetic strategy to label Gli1+ ASCs while eliminating ectopic labeling in SMCs. The results from this dual lineage tracing approach demonstrated that Gli1+ ASCs do not contribute to the SMC population in atherosclerotic plaques. Instead, Gli1+ ASCs differentiate into a significant portion of SMCs vascular anastomosis injury, suggesting their role is context-dependent. These findings challenge current paradigms and highlight the need to reconsider cellular targets for therapeutic interventions in atherosclerosis.
2026-02-01 | GSE310863 | GEO
Project description:Vascular smooth muscle cells (VSMCs) play a central role in the development of atherosclerosis due in part to their capability to phenotypically transition into either a protective or harmful state. However, the ability to identify and trace VSMCs and their progeny in vivo is limited due to the lack of well-defined VSMC cell surface markers. Therefore, investigations into VSMC fate must utilize lineage-tracing mouse models, which are time-consuming and challenging to generate and not feasible in humans. Here, we employed CITE-seq to characterize the phenotypic expression of 119 cell surface proteins in mouse atherosclerosis. We found that CD200 is a highly expressed and specific marker of VSMCs, which persists even with phenotypic modulation. We validated our findings using a combination of flow cytometry, qPCR, and immunohistochemistry, all confirming that CD200 can identify and mark VSMCs and their derived cells in early to advanced mouse atherosclerotic lesions. Additionally, we describe a similar expression pattern of CD200 in human coronary and carotid atherosclerosis. Thus, our data support the use of CD200 as a lineage marker for VSMCs and VSMC-derived cells in mouse and human atherosclerosis.
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Project description:This project presents a spatial proteomic investigation of vascular smooth muscle cells (VSMCs) and atherosclerotic plaque regions in a diabetic mouse model of atherosclerosis (DMAS). Using ApoE-/- mice fed with a high-fat diet and treated with low-dose streptozotocin (STZ) to induce a diabetic phenotype, we performed laser capture microdissection (LCM) to separately isolate plaque regions and adjacent VSMC-rich areas of the aortic arch. Subsequently, spatially resolved proteomic profiling was carried out using LC-MS/MS, followed by quantitative analysis based on iBAQ values. Differentially expressed proteins between plaque and VSMC regions were identified and enriched pathway analysis revealed significant alterations in oxidative stress response, insulin signaling, mitochondrial function, RNA transport, and extracellular matrix remodeling under diabetic conditions. Of particular interest, the spatial proteomics data highlighted a marked downregulation of the nuclear pore complex protein Nup93 in VSMCs from diabetic mice, implicating impaired nuclear transport and dysregulation of RNA alternative splicing. This finding was supported by transcriptomic integration and functional analyses that revealed aberrant splicing of SerpinE2, a gene associated with cell proliferation and ECM accumulation. This dataset provides region-specific, high-resolution proteomic profiles of vascular tissues in a diabetic atherosclerosis model. It serves as a valuable resource for investigating the spatial heterogeneity of vascular pathology and the molecular mechanisms underlying diabetes-accelerated atherosclerosis. The raw and processed data can be used to explore protein expression dynamics, identify spatiotemporal biomarkers, and validate candidate targets such as Nup93 and SerpinE2 involved in VSMC phenotypic switching.
2025-09-29 | PXD063231 | Pride