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  • 1
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    Abstract 9929: Epigenome-Wide-Association-Study Characterizes DNA Methylation Changes Associated With Lung and Right Ventricle Dysfunction in Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with pulmonary arteries remodeling and right ventricle (RV) dysfunction. Epigenetic dysregulation, including altered DNA methylation (DNAm), promotes PAH. However, the DNAm changes associated with PAH remain unexplored in human PAH RV and lungs. We conducted an exploratory study using human lung and RV samples to characterize the DNA methylome and transcriptomic changes associated with PAH. Methods/Results: We observed that PAH is associated with substantial changes in the DNAm landscape in both organs. We identified 88 identical differentially methylated probe (DMP) in both PAH Lungs and RV. Functionally, we observed that 65, and 76 of those DMP correlate with myocardial fibrosis and adverse pulmonary vascular remodeling, respectively. Then we clustered DMP onto functional differentially methylated region (DMR) and reported that 41% and 11.5% of the genes carrying a DMR are differentially expressed in PAH RV and lungs, respectively. Gene ontology analysis suggests that both impaired DNAm (DNA methylome) and genes expression (RNA sequencing) observed in PAH regulate biological functions related to inflammation, fibrosis, cell proliferation and vascular remodeling. Impaired DNAm landscape observed in PAH RV and lung is associated with the disease severity and contributes to 4.1% and 2.7% of the whole transcriptomic reprograming associated with PAH development in RV and lungs samples, respectively. Despite the modest overlap between DNAm and transcriptomic changes, we observed that DNAm affects genes and molecular pathways involved in PAH development. Conclusion: Although exploratory, our study is the first to characterize the DNAm and transcriptomic change associated with PAH in human RV and lung. Our data suggest that impaired DNAm landscape might contribute to the disease development/severity.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.9929
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 2
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    Abstract 13912: 17-Beta-Estradiol Directly Regulates Microtubule Dynamics: New Insights Into Sex-Differences in Right Ventricular Function in Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Introduction: Female sex is associated with better right ventricular (RV) function in pulmonary hypertension (PH). The female sex hormone 17-beta-estradiol is postulated to mediate these differences, but the molecular mechanisms underlying these observations are incompletely defined. Interestingly, 17-beta-estradiol induces microtubule depolymerization in cell culture, which may be relevant to RV dysfunction because microtubule remodeling promotes RV dysfunction via dysregulation of junctophilin-2 (MT-JPH2 pathway). We speculate that 17-beta-estradiol modulates the MT-JPH2 pathway and preserves RV function in PH. Methods: Pressure-volume assessments quantified RV function in monocrotaline (MCT) and pulmonary artery-banded (PAB) rats. Immunoblots quantified the tubulin and junctophilin-2 protein content in RV extracts. Echocardiography quantified RV function by RV fractional area change for 379 human PH patients. Sedimentation experiments, fluorescence-based polymerization assessments, and total internal reflection fluorescence (TIRF) microscopy examined the effects of 17-beta-estradiol on microtubules. Results: Female sex results in better RV function and less dysregulation of the MT-JPH2 pathway in both MCT and PAB rats. Moreover, in human PH, female sex was associated with better RV function, which persisted after adjusting for afterload. 17-beta-estradiol inhibited microtubule polymerization in vitro and TIRF microscopy showed 17-beta-estradiol localized to microtubule tips and prevented further microtubule polymerization. Conclusions: Preclinical and human studies show that females are better able to tolerate RV pressure overload. There are blunted microtubule-mediated t-tubule remodeling and preserved RV function in female MCT and PAB rats. In human PH, females have better RV function. These findings may be due to 17-beta-estradiol directly regulating microtubule dynamics as shown by sedimentation and polymerization assays and TIRF microscopy. These results provide additional insights into sex-differences in RV function in PH.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.13912
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 3
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    Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. 15 ( 2020-10-13), p. 1464-1484
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. 15 ( 2020-10-13), p. 1464-1484
    Abstract: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.120.047626
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 4
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    MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype
    American Thoracic Society ; 2017
    In:  American Journal of Respiratory and Critical Care Medicine Vol. 195, No. 4 ( 2017-02-15), p. 515-529
    Details
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 195, No. 4 ( 2017-02-15), p. 515-529
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    URL: Article
    DOI: 10.1164/rccm.201604-0814OC
    RVK:
    XA 21200
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2017
    detail.hit.zdb_id: 1468352-0
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  • 5
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    Abstract 17245: Deficiency of Tet Methylcytosine Dioxygenase 2 (tet2),A Key Enzyme in Cytosine Demethylation,Is an Epigenetic Driver of Inflammation and Disease Progression in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. Suppl_1 ( 2018-11-06)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. Suppl_1 ( 2018-11-06)
    Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by remodelling of distal pulmonary arteries associated with inflammation, endothelial cells (EC) dysfunction and a pro-proliferative/anti-apoptotic phenotype in pulmonary arterial smooth muscle cells (PASMC). Tet methylcytosine dioxygenase 2 (Tet2) is a key enzyme in cytosine demethylation that is crucial for epigenetic control of gene expression. Deficiency of Tet2 expression in myeloid cellsresults in increased inflammatory cytokine levels. Moreover, impaired Tet2 expression in EC has also been associated with decreased autophagy, as well as EC dysfunction. In addition, Tet2 silencing contributes to pro-proliferative phenotype of SMC. Thus, we hypothesized that Tet2 deletion would contribute to PAH by upregulation of inflammation and induction of PASMC proliferation and EC dysfunction. Methods and Results: To assess the ability of Tet2 deficiency to induce PAH we assessed cardiopulmonary hemodynamics in a conditional hematopoietic and endothelial cells Tet2 -/- mouse model. Tet2 -/- mice developed PAH associated with significant increases of right ventricular systolic pressure (RVSP), elevation of total pulmonary resistance (TPR) and increased vascular wall thickness of distal pulmonary arteries. Tet2 -/- lung tissue as well as macrophages and EC sorted from the lung displayed aberrant inflammatory cytokine signalling with robust overexpression of IL1βnoted on a Nanostring immune gene expression panel. In vitro IL1βincreased PASMC proliferation measured using EDU. Downregulation of TET2 in PASMC using siRNA resulted in a similar PAH-like phenotype. Moreover, lung from Tet2 -/- mice exhibited an alteration of vasoactive mediator gene expression (increased endothelin-1 (ET1), Arginase 2 (Arg2) and decreased eNOS). Finally we showed that downregulation of Tet2 (achieved by nebulization of si-Tet2) in rats with monocrotaline-induced PAH exacerbated disease severity (increasing TPR adverse pulmonary vascular remodelling).This phenotype was independent of the sex, was associated with a moderate decrease in RV function but had no significant effect on LV hemodynamic parameters. Conclusions: Tet2 is a protective epigenetic regulator that when conditionally downregulated in hematopoietic and endothelial cells leads toPAH by inducing a state of inflammation that contributes to PASMC proliferation and EC dysfunction which drives adverse pulmonary vascular remodelling.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.138.suppl_1.17245
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 6
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    Abstract 16016: Role For Macitentan in Angiogenesis of Right Ventricle, Peripheral Muscle and Lungs in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 132, No. suppl_3 ( 2015-11-10)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
    Abstract: Background: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by remodeling of distal pulmonary arteries (PA) leading to increased mean PA pressure, subsequent right ventricular (RV) failure and ultimately death of patients. Impaired angiogenesis is now recognized as a major factor in PAH etiology. It contributes not only to the decrease in lung perfusion but also to a rarefaction of the capillary network within the skeletal muscle and RV leading to exercise intolerance and RV failure. Several studies have suggested that endothelin-1 (ET-1) contributes to decrease angiogenesis in PAH. In light of these observations, we hypothesized that macitentan, an ET-1 receptors blocker, improves PAH by promoting angiogenesis in lungs, RV and skeletal muscles. Methods/Results: In the Sugen/hypoxia rat model of PAH, we demonstrated by right catheterization in closed chest rats that compared to vehicle treated animals, daily treatment during two weeks with macitentan (30 mg/kg) decreases significantly mean PA pressure (n=8-20; p 〈 0.01) and total pulmonary resistance (n=8-20; p 〈 0.05) and improves cardiac output, stroke volume (n=7-17; p 〈 0.05) and RV hypertrophy measured by echo (n=6-10; p 〈 0.05). These effects were associated with an increase of 2.9 fold in lung blood perfusion (n=6), 4.1 fold in quadriceps perfusion (n=5-7) and 1.5 fold in right ventricle perfusion (n=5-6) measured in vivo by micro CT angiogram (p 〈 0.05). Both in vivo lectin perfusion (n=4-10; p 〈 0.05) and immunologic CD31 staining (n=4-5; p 〈 0.05) confirmed these findings. In the lungs, the hemodynamic and perfusion improvements were associated with decreased vascular remodeling (H & E) (n=6-17; p 〈 0.01). In vitro, using primary cultured human endothelial cells isolated from distal PA (PAEC) and RV (RVEC), we showed that macitentan decreases PAH-PAEC proliferation (Ki67 assay) and resistance to apoptosis (TUNEL assay), while increasing angiogenesis capacity of healthy PAEC and RVEC (matrigel assay). Conclusion: Our data provide structural and functional evidence that ET-1 receptor inhibition with macitentan may improve PAH by promoting angiogenesis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.132.suppl_3.16016
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 7
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    Abstract 10900: Implication of the Post-Translational Formation of Hypusine in Eif5a in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Pulmonary Arterial Hypertension (PAH) is characterized by progressive pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) of PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties, many of them containing proline/glycine-rich patterns. Strikingly, eIF5A is the only protein containing the unique, polyamine-derived amino acid hypusine, which is required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased eiF5A Hyp in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and fibroproliferative capacity, leading to pulmonary vascular remodeling. Data derived from a comparative proteomic analysis (LC-MSMS) between normal and PAH-PASMCs and confirmed by Western blot indicate that DHPS and DOHH are overexpressed in PAH-PASMCs compared to controls (p 〈 0.05). Consistently, both total and hypusinated forms of eIF5A were found up-regulated in dissected PAs and PASMCs from PAH patients and animal models (MCT and Su/Hx rats, p 〈 0.05). In vitro , inhibition of DHPS and DOHH, using GC7 and ciclopirox, respectively, significantly attenuates PAH-PASMCs survival and proliferation, (Annexin V; Ki67 labeling and EdU incorporation, p 〈 0.01). These effects were confirmed by a reduced expression eiF5A Hyp , MCM2, PCNA and Survivin (p 〈 0.01) and a downregulation of BRD4, EP300 and COL1, three factors implicated in PAH containing proline/glycine-rich patterns. In vivo , inhibition of DHPS using GC7 in MCT rats with established PAH improves hemodynamics (RVSP, mPAP, CO, p 〈 0.05) and vascular remodeling (EVG, p 〈 0.05). Furthermore, preliminary data indicate that smooth muscle cells-targeted inactivation of one allele of Dhps tends to confer protection against Su/Hx-induced PAH in mice. We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.10900
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 8
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    Mir‐126 dependent alteration of angiogenesis contributes to right ventricle failure in pulmonary arterial hypertension (868.2)
    Wiley ; 2014
    In:  The FASEB Journal Vol. 28, No. S1 ( 2014-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 28, No. S1 ( 2014-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v28.S1
    DOI: 10.1096/fasebj.28.1_supplement.868.2
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 9
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    Abstract 150: Targeting The Lipogenic Enzyme ATP Citrate Lyase As A Potential Therapy Against Coronary Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 43, No. Suppl_1 ( 2023-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. Suppl_1 ( 2023-05)
    Abstract: Introduction: Coronary artery disease (CAD) such as coronary stenosis and intra vein graft stenosis are characterized by a cancer-like pro-proliferative and apoptosis-resistant phenotype of smooth muscle cells (SMCs), fueled by a metabolic shift toward glycolysis and interconnected global changes in the epigenetic landscape. The nucleo-cytoplasmic enzyme ATP Citrate Lyase (ACLY) has recently emerged as a key player and therapeutic target in cancer by favoring Warburg effect, lipid synthesis and chromatin remodeling. However, its role in CAD is still unknown. We hypothesized that ACLY is upregulated in CAD and supports the abnormal phenotype of CAD-CoASMCs. Methods and Results: ACLY expression positively correlates with vascular remodeling (aSMA labeling) in human distal coronary artery (CoAs, p 〈 0,01) as well as in dog saphenous vein (SV) graft from bypass surgery (p 〈 0,05). Increased expression and activation (phosphorylation) of ACLY were also observed in CoASMCs isolated from CAD patients (immunoblot, p 〈 0,01) with preferential localization in the nucleus (immunofluorescence ACLY labelling (p 〈 0,001)). Pharmacological (BMS303141) or molecular (siRNA) ACLY inhibition resulted in decreased survival, proliferation (immunoblot: PCNA, MCM2 and SURVIVIN (p 〈 0,05) & immunofluorescence Ki67 and Annexin V labelling (p 〈 0,001)), histones acetylation (immunoblot: acH3K27 and acH4 (p 〈 0,05)) and reversed Warburg effect (immunoblot: pPDH, LDHA, PFKBP3 (p 〈 0,01) & seahorse assays (p 〈 0,05)) of CAD-CoASMC. RNA sequencing analysis showed that ACLY molecular inhibition in CAD-CoASMC mostly affectes cell cycle and cell proliferation pathways. Ex-vivo, ACLY inhibition attenuates vascular remodeling (EVG staining) in human CoAs and SVs rings denuded of endothelial cells and exposed to growth factors (p 〈 0,05). In vivo, SMS-targeted loss of Acly in mice model of carotid artery denudation injury prevents vascular remodeling (p 〈 0,05). Same results are observed with pharmacological inhibition of ACLY (BMS303141 & bempedoic acid) in carotid artery wire injury rat model (p 〈 0,05). Conclusion: We demonstrated that ACLY is implicated in vascular remodeling in CAD and its Pharmacological inhibition may represent a novel avenue as therapeutic treatment.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.43.suppl_1.150
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1494427-3
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  • 10
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    17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
    American Society for Clinical Investigation ; 2021
    In:  Journal of Clinical Investigation Vol. 131, No. 6 ( 2021-3-15)
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 131, No. 6 ( 2021-3-15)
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    DOI: 10.1172/JCI129433
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2021
    detail.hit.zdb_id: 2018375-6
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