Gut microbial composition and functional capacity in patients with arterial stiffness
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ABSTRACT:
PROVIDER: PRJEB49672 | ENA |
REPOSITORIES: ENA
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Project description:We are investigating of role of RhoBTB1 in vascular smooth muscle cells. Restoring RhoBTB1 expression in mouse aorta reversed the established arterial stiffness but not hypertension caused by angiotensin II (Ang-II). To investigate the underlying mechanism by which RhoBTB1 reversed arterial stiffness, we performed bulk RNA-sequencing using aorta from four groups: control /RhoBTB1 transgenic mice treated with/without Ang-II.
2022-04-08 | GSE189003 | GEO
Project description:RhoBTB1 Reverses Established Arterial Stiffness in Angiotensin II Hypertension
| PRJNA781123 | ENA
Project description:BACKGROUND: Previous genomic studies with human tissues have compared differential gene expression between 2 conditions (ie, normal versus diseased) to identify altered gene expression in a binary manner; however, a potentially more informative approach is to correlate the levels of gene expression with quantitative physiological parameters. METHODS AND RESULTS: In this study, we have used this approach to examine genes whose expression correlates with arterial stiffness in human aortic specimens. Our data identify 2 distinct groups of genes, those associated with cell signaling and those associated with the mechanical regulation of vascular structure (cytoskeletal-cell membrane-extracellular matrix). Although previous studies have concentrated on the contribution of the latter group toward arterial stiffness, our data suggest that changes in expression of signaling molecules play an equally important role. Alterations in the profiles of signaling molecules could be involved in the regulation of cell cytoskeletal organization, cell-matrix interactions, or the contractile state of the cell. CONCLUSIONS: Although the influence of smooth muscle contraction/relaxation on arterial stiffness could be controversial, our provocative data would suggest that further studies on this subject are indicated.<br><br>Note that files GSM6179.txt and GSM6182.txt as imported from GEO are identical.
2007-12-13 | E-GEOD-420 | biostudies-arrayexpress
Project description:BACKGROUND: Previous genomic studies with human tissues have compared differential gene expression between 2 conditions (ie, normal versus diseased) to identify altered gene expression in a binary manner; however, a potentially more informative approach is to correlate the levels of gene expression with quantitative physiological parameters. METHODS AND RESULTS: In this study, we have used this approach to examine genes whose expression correlates with arterial stiffness in human aortic specimens. Our data identify 2 distinct groups of genes, those associated with cell signaling and those associated with the mechanical regulation of vascular structure (cytoskeletal-cell membrane-extracellular matrix). Although previous studies have concentrated on the contribution of the latter group toward arterial stiffness, our data suggest that changes in expression of signaling molecules play an equally important role. Alterations in the profiles of signaling molecules could be involved in the regulation of cell cytoskeletal organization, cell-matrix interactions, or the contractile state of the cell. CONCLUSIONS: Although the influence of smooth muscle contraction/relaxation on arterial stiffness could be controversial, our provocative data would suggest that further studies on this subject are indicated. Keywords: other
2003-08-28 | GSE420 | GEO
Project description:Arterial stiffness is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms are not well understood. Wall shear stress and shear-sensitive genes may promote arterial stiffening through clinically important signaling pathways. Our goal was to identify how disturbed blood flow leads to arterial stiffness using the mouse partial carotid ligation model. Here we used our in vivo partial carotid ligation model to induce d-flow in the LCA while the contralateral RCA continues to experience stable laminar flow using the C57BL/6x129SvEv mice, TSP-1 knockout (KO), and C57Bl/6J mice. We compared these to aged (80 week) mice which had increased arterial stiffness due to aging. Changes in gene expression were identified using microarrays that were performed on the endothelial-enriched RNA isolated from the carotids exposed to stable flow (RCA) and compared to disturbed flow (LCA). Arterial stiffness was determined ex vivo by biaxial mechanical testing and in vivo by ultrasound techniques. Myointimal hyperplasia and immunohistochemistry were performed in sectioned carotid arteries. In vitro testing of signaling pathways utilized oscillatory and laminar wall shear stress. Human arteries were tested ex vivo to validate critical results found in the animal model.
2017-09-01 | GSE87199 | GEO
Project description:Purpose: Arterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LMNAG609G mouse model of HGPS recapitulates the premature arterial stiffening seen in human HGPS. To gain a better understanding of potential stiffness-regulators in LMNAG609G mice, we performed RNA-sequencing analysis on cleaned descending aortas from 2- and 24-month WT and 2-month LMNAG609G mice on a C57BL6 background. Methods: Descending aortas containing the intimal, medial and adventitial layers were isolated from 2- and 24-month male WT and 2-month HGPS mice, and RNA was extracted using the RNeasy Plus Micro kit (Qiagen 74034). The high-throughput library was prepared using the TruSeq stranded total RNA (ribo-Zero) kit (Illumina 20037135). Paired-end sequencing was performed on a HiSeq4000 Sequencing System (Illumina) and generated 14-30 million reads/sample.
2021-02-09 | GSE165409 | GEO
Project description:SMCs express plasminogen activator inhibitor-1 (PAI-1), which regulates SMC function and vascular remodeling. However, whether PAI-1 controls SMC cytoskeletal dynamics and stiffness is unknown, and the causal role of PAI-1 in arterial stiffening is undefined. SMCs from human coronary arteries and aortae of wild-type vs. PAI-1-deficient mice were cultured with or without PAI-039, a specific PAI-1 inhibitor, after which cell stiffness was measured by atomic force microscopy, filamentous actin structures were assessed by confocal microscopy, and the activities cofilin, LIM domain kinase 1 (LIMK), slingshot homolog 1 (SSH), and AMP-activated protein kinase (AMPK) were measured. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. Effects of PAI-039 on aortic stiffness were assessed by pulse wave velocity. PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by significant decreases in cytoplasmic actin filaments. Similar effects were observed in wild-type, but not in PAI-1-deficient SMCs. Mechanistically, PAI-039 significantly increased the activity of cofilin, an actin depolymerase, in SMCs expressing PAI-1, but not in PAI-1-deficient cells. PAI-039 had no significant effects on LIMK or SSH activity. RNA-sequencing analysis suggested that PAI-039 up-regulates AMPK signaling in SMCs, which was confirmed by western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness without significantly altering peri-aortic fibrosis. PAI-039 decreases intrinsic SMC stiffness by reducing cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacologic inhibition of PAI-1 has potential to treat cardiovascular diseases mediated by accelerated arterial stiffening.
2023-02-23 | GSE225644 | GEO
Project description:Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase
| PRJNA694470 | ENA
Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.
2024-06-16 | PXD046001 | Pride
Project description:The Rho family GTPases, Rac and Rho, play critical roles in transmitting mechanical information contained within the extracellular matrix (ECM) to the cell. Rac and Rho have well described roles in regulating stiffness-dependent actin remodeling, proliferation and motility. However, much less is known about the relative roles of these GTPases in stiffness-dependent transcription, particularly at the genome-wide level. Here, we selectively inhibited Rac and Rho in mouse embryonic fibroblasts cultured on deformable substrata and used RNA sequencing to elucidate and compare the contribution of these GTPases to the early transcriptional response to ECM stiffness. Surprisingly, we found that the stiffness-dependent activation of Rac is dominant over Rho in the initial transcriptional response to ECM stiffness. We also identified Activating Transcription Factor 3 (ATF3) as a major target of stiffness/Rac-mediated signaling and show that ATF3 repression by ECM stiffness helps to explain how the stiffness-dependent activation of Rac results in the induction of cyclin D1.
2023-10-04 | GSE236266 | GEO