Differences in Quantitative Crotonylated Protein Profiling of Human Arterial and Venous Grafts for Coronary Artery Bypass Surgery with Implications to Long-term Patency
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Guowei-He
PROVIDER: PXD026404 | iProX | Tue Jun 01 00:00:00 BST 2021
REPOSITORIES: iProX
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Project description:Endothelial cells (EC) lining arteries and veins have distinct molecular and functional signatures. The (epi)genetic regulatory mechanisms underlying this heterogeneity in human EC are incompletely understood. Using genome-wide microarray screening we established a specific fingerprint of freshly isolated arterial (HUAEC) and venous EC (HUVEC) from human umbilical cord comprising 64 arterial and 12 venous genes, representing distinct functions and pathways. Among the arterial genes were 8 transcription factors, including HEY2, a downstream target of Notch signaling and the current ‘golden standard’ pathway for arterial EC specification. Short-term culture of HUAEC or HUVEC abrogated differential gene expression resulting in a default state. Erasure of arterial gene expression was at least in part due to loss of canonical Notch activity and HEY2 expression. Notably, nCounter analysis revealed that restoring HEY2 expression or Delta-like 4 (Dll4)-induced Notch signaling in cultured HUVEC or HUAEC only partially reinstated the arterial EC gene signature while combined overexpression of the 8 transcription factors restored this fingerprint much more robustly. Each transcription factor had a different impact on gene regulation, with some stimulating only few and others boosting a large proportion of arterial genes. Interestingly, although there was some overlap and cross-regulation, the transcription factors largely complemented each other in regulating the arterial EC gene profile. Thus, our study showed that Notch signaling determines only part of the arterial EC signature and identified additional novel and complementary transcriptional players in the complex regulation of human arteriovenous EC identity To identify an arteriovenous (AV) fingerprint in human endothelial cells (EC) across different vascular beds, we used microarrays on RNA from 38 EC samples corresponding to 6 cultured human arterial-EC types (hepatic artery EC or HHAEC, N=3; aorta EC or HAEC, N=2; coronary artery EC or HCAEC, N=2; iliac artery EC or HIAEC, N=2; pulmonary artery EC or HPAEC, N=3; and umbilical artery EC or HUAEC-C, N=5), 4 cultured human venous-EC types (hepatic vein EC or HHVEC, N=3; iliac vein EC or HIVEC, N=3; pulmonary vein EC or HPVEC, N=2; and umbilical vein EC or HUVEC-C, N=5), freshly isolated HUAEC (HUAEC-F, N=4) and freshly isolated HUVEC (HUVEC-F, N=4). Due to the difficulty to obtain biopsies from healthy donors, we did not have access to freshly isolated aEC or vEC matched for all cultured EC types.
2014-01-07 | E-GEOD-43475 | biostudies-arrayexpress
Project description:Pulmonary arterial hypertension (PAH) is characterized by severe obstruction of small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induced severe occlusive arterial hypertrophy in the lung, which was mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulated around blood vessels and produced IL-5, leading to perivascular eosinophil recruitment. In this study, we further characterized IL-33-induced pulmonary arterial hypertrophy. We first demonstrated that long-term IL-33 administration caused an increase in the right ventricular pressure. In IL-33 deficient mice, pulmonary arterial hypertrophy mediated by eggs of Schistosoma mansoni (S. mansoni) was attenuated, accompanied with partial reduction in ILC2s, eosinophils and CD4+ T cells. In addition, proteomic analysis revealed dramatic changes in urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin like alpha (RELM), a pulmonary hypertension-related molecule, in the urine was commonly detected in both treatments. Large amounts of RELM were observed in the lung from IL-33-treated mice. These observations support that IL-33-induced pulmonary arterial hypertrophy is a useful model to study the mechanism underlying development of PAH and expolar biomarkers to indicate the onset of PAH.
2024-09-27 | PXD055773 | JPOST Repository
Project description:Mitotic fission is increased in hyperproliferative, apoptosis-resistant diseases, such as pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype includes activation of the fission mediator, dynamin related protein 1 (Drp1), which must complex with its adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore the role of their dysregulation in the pathogenesis of PAH. MiDs are increased in PAH PASMC. This accelerates Drp1-mediated mitotic fission, which increases cell proliferation and decreases apoptosis. Silencing MiDs (but not Fis1 or MFF) promotes mitochondrial fusion and G1-phase cell cycle arrest through an ERK1/2 and CDK4-dependent mechanism. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased microRNA-34a-3p (miR-34a-3p) expression. Circulatory miR34a-3p expression is decreased in PAH patients as well as in preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. We used microarrays to identify differences in miR expression in pulmonary artery smooth muscle cells (PASMC) taken from either pulmonary arterial hypertension patients or healthy controls
2018-01-31 | GSE108707 | GEO
Project description:CAV1 loss-of-function mutations have been associated with the development of pulmonary arterial hypertension (PAH). CAV1 is an integral component of endothelial caveolae, specialized lipid rafts that attach to the actin cytoskeleton and modulate receptor/signal transduction coupling. CAV1 loss in pulmonary artery endothelial cells produced a proliferative, hypermigratory cellular phenotype with a disrupted cytoskeletal architecture, mirroring known features of PAH pathobiology. Gene expression on Human Pulmonary Arterial Endothelial Cells (PAECs) transfected with non-targeting siRNA control pool or siRNA (ON-TARGET plus CAV1) in the presence or absence of TNF-alpha was evaluated
2021-02-24 | GSE138991 | GEO
Project description:Rationale: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure and vascular resistance, typically leading to right heart failure and death. Current therapies improve quality of life of the patients but have a modest effect on long-term survival. A detailed transcriptomics and systems biology view of the PAH lung is expected to provide new testable hypotheses for exploring novel treatments. Objectives: Complete transcriptomics analysis of PAH and control lung tissue to develop disease-specific and clinical data/tissue pathology gene expression classifiers from expression datasets. Gene expression data were integrated into pathway analyses. Methods: Gene expression microarray data was collected from 58 PAH and 25 control lung tissues. The strength of the dataset and its derived disease classifier was validated using multiple approaches. Pathways and upstream regulators analyses was completed with standard and novel graphical approaches. Measurements and Main Results: The PAH lung dataset identified expression patterns specific to PAH subtypes, clinical parameters, and lung pathology variables. Pathway analyses indicate the important global role tumor necrosis factor and transforming growth factor signaling pathways. In addition, novel upstream regulators and insight into the cellular and innate immune responses driving PAH were identified. Finally, WNT-signaling pathways may be a major determinant underlying the observed sex differences in PAH. Conclusion: This study provides a transcriptional framework for the PAH-diseased lung, supported by previously reported findings, and will be a valuable resource to PAH research community. Our investigation revealed novel potential targets and pathways amenable to further study in a variety of experimental systems.
2018-12-23 | GSE117261 | GEO
Project description:BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodeling and plexiform lesions. Cardiosphere derived cells (CDCs) are heart derived progenitor cells exhibiting anti inflammatory and immunomodulatory effects, are anti fibrotic, anti oxidative and anti apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation.
METHODS: The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH connective tissue disease (CTD ) and PAH human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n=6). Phase 1b was a double blind placebo controlled study (n=20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year.
FINDINGS: No short term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 hours monitored in hospital. There were no long term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favoring CDCs (n=16) compared to placebo (n=10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6 minute walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favoring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12 months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long term follow up through 12 months.
INTERPRETATION: Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDCs potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.
2023-11-06 | MSV000093323 | MassIVE
Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.
2018-08-10 | GSE106274 | GEO
Project description:The equine bloodworm, Strongylus vulgaris, is a highly pathogenic parasite causing potentially fatal vascular and intestinal damage. Parasites express and release microRNAs (miRNAs) for internal regulation and to modulate host immunity. The microRNAome (miRNAome) of S. vulgaris remains unannotated and the aim of this study was to annotate the miRNAome of 4th (L4) and 5th (L5) stage larvae of S. vulgaris and to examine differences in miRNA abundance between larval stages and sexes. Furthermore, we aimed to determine if miRNAs were detectable in excretory/secretory products (ESP) from larvae and in arterial tissue from their predilection site, the Cranial Mesenteric Artery (CMA). Larvae were collected from naturally infected foals, and categorized by sex and stage. A subset of larvae was snap-frozen, while the remaining were incubated and the excretory/secretory products (ESP) collected. Arterial tissue samples were collected from the CMA. Small RNA sequencing followed by a custom bioinformatic pipeline was used for annotation. We identified 142 S. vulgaris miRNAs in larvae and 136 in ESP. Significant differences in miRNA abundance were observed between larvae and ESP, and between L5 females (L5Fs) and L5 males (L5Ms), L4s and L5Fs and L4s and L5Ms. No differences were found between L4s and L5s overall. In ESP, several miRNAs were differentially abundant across all groups. Validation through quantitative real-time PCR (qPCR) detected selected miRNAs and their differential abundance in larvae and ESP. One parasite-derived miRNA was detected in some of the horse arterial tissue samples but at very low levels. This study provided the first annotation of the S. vulgaris miRNAome. Most of the annotated larvae miRNAs were also detectable in ESP and differences in miRNA abundance between sexes were found for larvae, and between sexes and stages for ESP. Parasite-derived miRNAs were, however, not consistently detectable in the surrounding host arterial tissue.
2024-12-12 | GSE266592 | GEO
Project description:Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. Collaterals are artery-to-artery or arteriole-to-arteriole interconnections that can bypass an occlusion by providing an alternative route for blood flow to the affected tissue. The increased flow and sheer stress initiate processes that result in the remodeling (arteriogenesis) of these vessels into efficient conductance arteries. Here we report that the mixed-lineage kinase (MLK) pathway activates cJun NH2-terminal kinase (JNK) in endothelial cells. Disruption of Mlk2/3 or Jnk1/2 genes caused severe blockade of blood flow and failure to recover in the femoral artery ligation model of hindlimb ischemia because of abnormal collateral arteries. We show that the MLK-JNK pathway is essential for patterning and maturation of collateral arteries during development, but this pathway is not required for angiogenesis or arteriogenesis in adults. JNK in endothelial cells promotes Delta-like 4-induced Notch signaling and suppresses excessive sprouting angiogenesis during development. This function of the MLK-JNK pathway contributes to normal formation of native collateral arteries. The MLK-JNK pathway is therefore a key regulatory mechanism for vascular development. These data highlight the crucial importance of the collateral circulation in the response to arterial occlusive diseases. RNA-seq analysis of mouse lung endothelial cells (MLEC) of the following genotypes Cdh5-Cre+ Jnk1+/+ Jnk2+/+ Jnk3-/-(ECtrl), Cdh5-Cre- Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (EfCtrl), and Cdh5-Cre+ Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (E3KO). Three separate samples from mouse lung endothelial cells of each genotype were analyzed.
2016-08-09 | E-GEOD-71159 | biostudies-arrayexpress
Project description:In this placebo-controlled randomized controlled trial, we tested whether remote ischemic preconditioning (RIPC) elicited by four 5-minute cycles of 300 mmHg of cuff inflation/deflation of the lower limb would reduce myocardial necrosis in isoflurane-anesthetized patients undergoing on-pump coronary artery bypass graft surgery. Secondary outcomes were the perioperative release of the biomarkers NTproBNP, hsCRP, S100, atrial transcriptional profiles, and short- and long-term clinical outcomes. RIPC with concomitantly applied isoflurane did not affect the release of biomarkers or clinical outcome. NTproBNP release correlated with isoflurane- but not RIPC-induced transcriptional changes.
2012-10-12 | GSE29396 | GEO