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.
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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
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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
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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:Vascular smooth muscle cells participate in the formation and development of fibrous cap in the early stage of atherosclerosis,Notch3 plays an important role in maintaining the phenotypic stability of VSMCs.However,the molecular mechanism between Notch3 and VSMCs is not fully understood
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Project description:Vascular calcification is a hallmark of atherosclerosis and end-stage renal disease (ESRD). However, the molecular mechanism of vascular calcification is poorly understood. Diabetes mellitus is increasingly recognized as the most important cause for atherosclerosis and ESRD. Emerging evidence supports the concept that vascular calcification resembles the process of osteogenesis, in which the vascular smooth muscle cells (VSMC) undergo osteochondrogenic differentiation. Recently, we have established an in vitro calcification system with primary mouse VSMC. With the use of osteogenic stimuli, we induced trans-differentiation of primary mouse VSMC into bone-like cells. Interestingly stroptozotocin (STZ), O-GlcNAcase inhibitor and a drug that has been used to induce diabetes in mice, was able to induce calcification of VSMC and the expression of the osteogenic transcription factor Runx2, suggesting glycosylation may be involved in regulation of Runx2. We have reported an essential role of Runx2 in oxidative stress-induce VSMC calcification and have recently generated a tissue specific mouse with Runx2 ablation in smooth muscle cells. Therefore, we will use STZ and other relevant reagents in the glucose synthesis/metabolism pathways as stimuli for VSMC calcification to characterize the glycogene profiles during VSMC calcification. Results from VSMC of Runx2 knockout mice will be compared with those from control mice to determine the regulation of calcification-associated glycogenes by Runx2 in response to STZ. These studies will provide foundation for further mechanistic studies and may lead to identification of novel strategies and targets for diabetes-induced vascular calcification. To examine vascular smooth muscle cells (VSMC) under two conditions: 1) wild-type VSMC differentiated into bone-like cells with osteogenic media, 2) wild-type VSMC treated with STZ and osteogenic media
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