Shear Stress and NOTCH1 Regulate Calcification Related Genes in Human Aortic Valve Endothelium
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE47160 | GEO | 2015/05/16
SECONDARY ACCESSION(S): PRJNA204846
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-05-16 | E-GEOD-47160 | biostudies-arrayexpress
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium. Primary human aortic valve endothelium was subjected to 4 conditions in vitro. 1) Control siRNA, No shear stress. 2) NOTCH1 siRNA, No shear stress. 3) Control siRNA, 15 dynes/cm2 shear stress. 4) NOTCH1 siRNA, 15 dynes/cm2 shear stress. Triplicates of each condition were pooled for library perp and sequencing
2015-05-16 | E-GEOD-47157 | biostudies-arrayexpress
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium.
2015-05-16 | GSE47152 | GEO
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium.
2015-05-16 | GSE47157 | GEO
Project description:Valvular and vascular calcification are common causes of cardiovascular morbidity and mortality. Developing effective treatments requires understanding the molecular underpinnings of these processes. Shear stress is thought to play a role in inhibiting calcification. Furthermore, NOTCH1 regulates vascular and valvular endothelium, and human mutations in NOTCH1 can cause calcific aortic valve disease. Here, we determined the genome-wide impact of altering shear stress and NOTCH signaling on human aortic valve endothelium. mRNA-sequencing of primary human aortic valve endothelial cells (HAVECs) with or without knockdown of NOTCH1, in the presence or absence of shear stress, revealed NOTCH1-dependency of the atherosclerosis-related gene connexin 40 (GJA5), and numerous repressors of endochondral ossification. Among these, matrix gla protein (MGP) is highly expressed in aortic valve and vasculature, and inhibits soft tissue calcification by sequestering bone morphogenetic proteins (BMPs). Altering NOTCH1 levels affected MGP mRNA and protein in HAVECs. Furthermore, shear stress activated NOTCH signaling and MGP in a NOTCH1-dependent manner. NOTCH1 positively regulated endothelial MGP in vivo through specific binding motifs upstream of MGP. Our studies suggest that shear stress activates NOTCH1 in primary human aortic valve endothelial cells leading to downregulation of osteoblast-like gene networks that play a role in tissue calcification.
| S-EPMC4468000 | biostudies-literature
Project description:BackgroundBicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified.MethodsWe constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway.ResultsFinite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.
| S-EPMC9997191 | biostudies-literature
Project description:OBJECTIVES:Bicuspid aortic valve, characterized by valve malformation and risk for aortopathy, displays profound alteration in systolic aortic outflow and wall shear stress distribution. The present study performed 4-dimensional flow magnetic resonance imaging in patients with bicuspid aortic valve with right-left cusp fusion, focusing on the impact of valve function on hemodynamic status within the ascending aorta. METHODS:Four-dimensional flow magnetic resonance imaging was performed in 50 subjects with right-left bicuspid aortic valve and 15 age- and aortic size-matched controls with tricuspid aortic valve. Patients with bicuspid aortic valve were categorized into 3 groups according to their aortic valve function as follows: bicuspid aortic valve with no more than mild aortic valve dysfunction (bicuspid aortic valve control, n = 20), bicuspid aortic valve with severe aortic insufficiency (n = 15), and bicuspid aortic valve with severe aortic stenosis (n = 15). RESULTS:All patients with right-left bicuspid aortic valve exhibited peak wall shear stress at the right-anterior position of the ascending aorta (bicuspid aortic valve vs trileaflet aortic valve at the right-anterior position: 0.91 ± 0.23 N/m2 vs 0.43 ± 0.12 N/m2, P < .001) with no distinct alteration between bicuspid aortic valve with severe aortic insufficiency and bicuspid aortic valve with severe aortic stenosis. The predominance of dilatation involving the tubular ascending aorta (82%, type 2 aortopathy) persisted, with or without valve dysfunction. Compared with bicuspid aortic valve control subjects, the bicuspid aortic valve with severe aortic insufficiency group displayed universally elevated wall shear stress (0.75 ± 0.12 N/m2 vs 0.57 ± 0.09 N/m2, P < .01) in the ascending aorta, which was associated with elevated cardiac stroke volume (P < .05). The bicuspid aortic valve with severe aortic stenosis group showed elevated flow eccentricity in the form of significantly increased standard deviation of circumferential wall shear stress, which correlated with markedly increased peak aortic valve velocity (P < .01). CONCLUSIONS:The location of peak aortic wall shear stress and type of aortopathy remained homogeneous among patients with right-left bicuspid aortic valve irrespective of valve dysfunction. Severe aortic insufficiency or stenosis resulted in further elevated aortic wall shear stress and exaggerated flow eccentricity.
| S-EPMC5438758 | biostudies-literature
Project description:BackgroundBicuspid aortic valve (BAV) disease leads to deviant helical flow patterns especially in the mid-ascending aorta (AAo), potentially causing wall alterations such as aortic dilation and dissection. Among others, wall shear stress (WSS) could contribute to the prediction of long-term outcome of patients with BAV. 4D flow in cardiovascular magnetic resonance (CMR) has been established as a valid method for flow visualization and WSS estimation. The aim of this study is to reevaluate flow patterns and WSS in patients with BAV 10 years after the initial evaluation.MethodsFifteen patients (median age 34.0 years) with BAV were re-evaluated 10 years after the initial study from 2008/2009 using 4D flow by CMR. Our particular patient cohort met the same inclusion criteria as in 2008/2009, all without enlargement of the aorta or valvular impairment at that time. Flow patterns, aortic diameters, WSS and distensibility were calculated in different aortic regions of interest (ROI) with dedicated software tools.ResultsIndexed aortic diameters in the descending aorta (DAo), but especially in the AAo did not change in the 10-year period. Median difference 0.05 cm/m2 (95% CI: 0.01 to 0.22; P=0.06) for AAo and median difference -0.08 cm/m2 (95% CI: -0.12 to 0.01; P=0.07) for DAo. WSS values were lower in 2018/2019 at all measured levels. Aortic distensibility decreased by median 25.6% in the AAo, while stiffness increased concordantly (median +23.6%).ConclusionsAfter a ten years' follow-up of patients with isolated BAV disease, indexed aortic diameters did not change in this patient cohort. WSS was lower compared to values generated 10 years earlier. Possibly a drop of WSS in BAV could serve as a marker for a benign long-term course and implementation of more conservative treatment strategies.
| S-EPMC9971286 | biostudies-literature
Project description:OBJECTIVES:The objectives of this study were to investigate an association between the magnitude of flow-mediated aortic wall shear stress (WSS) and medial wall histopathology in patients with bicuspid aortic valve (BAV) with aortopathy. METHODS:Patients with BAV (n = 27; 52 ± 15 years; 3 women; proximal thoracic aorta diameter = 4.4 ± 0.7 and 4.6 ± 0.5 cm) who underwent prophylactic aortic resection received preoperative 3-dimensional time-resolved phase-contrast magnetic resonance imaging with 3-dimensional velocity encoding to quantify WSS relative to a population of healthy age- and sex-matched tricuspid aortic valve control participants (n = 20). Quantitative histopathology was conducted on BAV aorta tissue samples resected at surgery (n = 93), and correlation was performed between elastic fiber thickness and in vivo aortic WSS as continuous variables. Validation of elastic fiber thickness was achieved by correlation relative to tissue stiffness determined using biaxial biomechanical testing (n = 22 samples). RESULTS:Elastic fibers were thinner and WSS was higher along the greater curvature compared with other circumferential regions (vs anterior wall: P = .003 and P = .0001, respectively; lesser curvature: both P = .001). Increased regional WSS was associated with decreased elastic fiber thickness (r = -0.25; P = .02). Patient stratification with subanalysis showed an increase in the correlation between WSS and histopathology with aortic valve stenosis (r = -0.36; P = .002) and smaller aortic diameters (<4.5 cm: r = -0.39; P = .03). Elastic fiber thinning was associated with circumferential stiffness (r = -0.41; P = .06). CONCLUSIONS:For patients with BAV, increased aortic valve-mediated WSS is significantly associated with elastic fiber thinning, particularly with aortic valve stenosis and in earlier stages of aortopathy. Elastic fiber thinning correlates with impaired tissue biomechanics. These novel findings further implicate valve-mediated hemodynamics in the progression of BAV aortopathy.
| S-EPMC6242768 | biostudies-literature
Project description:miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.
| S-EPMC6416061 | biostudies-literature