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  1. Article ; Online: Myocardial fibrosis and calcification are attenuated by microRNA-129-5p targeting Asporin and Sox9 in cardiac fibroblasts.

    Medzikovic, Lejla / Aryan, Laila / Ruffenach, Grégoire / Li, Min / Savalli, Nicoletta / Sun, Wasila / Sarji, Shervin / Hong, Jason / Sharma, Salil / Olcese, Riccardo / Fishbein, Gregory / Eghbali, Mansoureh

    JCI insight

    2023  Volume 8, Issue 9

    Abstract: Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, ... ...

    Abstract Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR-129-5p and upregulation of its targets small leucine-rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR-129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR-129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR-129-5p that inhibit downstream β-catenin expression. Chronic Angiotensin II infusion downregulated miR-129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR-129-5p mimic. Importantly, miR-129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR-129-5p/ASPN and miR-129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR-129-5p.
    MeSH term(s) Humans ; Mice ; Animals ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Cardiomyopathies/metabolism ; Fibroblasts/metabolism ; Heart Failure/metabolism ; Fibrosis ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/metabolism
    Chemical Substances MicroRNAs ; TCF21 protein, human ; Basic Helix-Loop-Helix Transcription Factors ; SOX9 protein, human ; SOX9 Transcription Factor ; Mirn129 microRNA, human ; MIRN129 microRNA, mouse
    Language English
    Publishing date 2023-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.168655
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Autonomic nervous system involvement in pulmonary arterial hypertension.

    Vaillancourt, Mylène / Chia, Pamela / Sarji, Shervin / Nguyen, Jason / Hoftman, Nir / Ruffenach, Gregoire / Eghbali, Mansoureh / Mahajan, Aman / Umar, Soban

    Respiratory research

    2017  Volume 18, Issue 1, Page(s) 201

    Abstract: Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has ... ...

    Abstract Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.
    MeSH term(s) Animals ; Autonomic Nervous System/physiopathology ; Humans ; Hypertension, Pulmonary/diagnosis ; Hypertension, Pulmonary/physiopathology ; Pulmonary Artery/physiology ; Pulmonary Artery/physiopathology ; Randomized Controlled Trials as Topic/methods ; Renin-Angiotensin System/physiology ; Ventricular Dysfunction, Right/diagnosis ; Ventricular Dysfunction, Right/physiopathology
    Language English
    Publishing date 2017--04
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2041675-1
    ISSN 1465-993X ; 1465-9921
    ISSN (online) 1465-993X
    ISSN 1465-9921
    DOI 10.1186/s12931-017-0679-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Y Chromosome Plays a Protective Role in Experimental Hypoxic Pulmonary Hypertension.

    Umar, Soban / Cunningham, Christine M / Itoh, Yuichiro / Moazeni, Shayan / Vaillancourt, Mylene / Sarji, Shervin / Centala, Alex / Arnold, Arthur P / Eghbali, Mansoureh

    American journal of respiratory and critical care medicine

    2017  Volume 197, Issue 7, Page(s) 952–955

    MeSH term(s) Animals ; Castration ; Disease Models, Animal ; Female ; Hypertension, Pulmonary/genetics ; Hypoxia/genetics ; Male ; Mice ; Severity of Illness Index ; Y Chromosome/genetics
    Language English
    Publishing date 2017-09-21
    Publishing country United States
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.201707-1345LE
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

    Ruffenach, Gregoire / Umar, Soban / Vaillancourt, Mylene / Hong, Jason / Cao, Nancy / Sarji, Shervin / Moazeni, Shayan / Cunningham, Christine M / Ardehali, Abbas / Reddy, Srinivasa T / Saggar, Rajan / Fishbein, Gregory / Eghbali, Mansoureh

    EMBO molecular medicine

    2019  Volume 11, Issue 9, Page(s) e10061

    Abstract: Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients ... ...

    Abstract Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non-fibrotic areas of PF-PH patient lungs compared to PF patients. The increased vascular wall thickness in PF-PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin-induced protein (PIP), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF-PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF-PH. We found Slug inhibition decreases PH severity in our animal model of PF-PH. Our study highlights the role of Slug/PIP axis in PF-PH.
    MeSH term(s) Adult ; Aged ; Animals ; Female ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/pathology ; Lung/metabolism ; Lung/pathology ; Macrophages/metabolism ; Male ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Middle Aged ; Myocytes, Smooth Muscle/metabolism ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Rats, Wistar ; Snail Family Transcription Factors/genetics ; Snail Family Transcription Factors/metabolism ; Young Adult
    Chemical Substances Membrane Transport Proteins ; PIP protein, human ; SNAI1 protein, human ; Snail Family Transcription Factors
    Language English
    Publishing date 2019-08-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.201810061
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Involvement of Low-Density Lipoprotein Receptor in the Pathogenesis of Pulmonary Hypertension.

    Umar, Soban / Ruffenach, Gregoire / Moazeni, Shayan / Vaillancourt, Mylene / Hong, Jason / Cunningham, Christine / Cao, Nancy / Navab, Sara / Sarji, Shervin / Li, Min / Lee, Lisa / Fishbein, Greg / Ardehali, Abbas / Navab, Mohamad / Reddy, Srinivasa T / Eghbali, Mansoureh

    Journal of the American Heart Association

    2020  Volume 9, Issue 2, Page(s) e012063

    Abstract: Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the ... ...

    Abstract Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the role of LDL-R in the development of PH and determined the efficacy of high-density lipoprotein mimetic peptide 4F in mitigating PH. Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL-R null (LDL-R knockout) mice (12-15 months old) were fed chow, Western diet (WD), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real-time quantitative reverse transcription-polymerase chain reaction, and histological analysis were performed. The effect of LDL-R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL-R and CD36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL, E06 immunoreactivity, and plasma oxidized LDL/LDL ratio. LDL-R knockout mice on WD developed PH, right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL-R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.
    MeSH term(s) Animals ; Apolipoprotein A-I/pharmacology ; CD36 Antigens/metabolism ; Case-Control Studies ; Cells, Cultured ; Disease Models, Animal ; Fibrosis ; Hemodynamics/drug effects ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/physiopathology ; Hypertension, Pulmonary/prevention & control ; Lipoproteins, LDL/metabolism ; Male ; Mice, Knockout ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Pulmonary Artery/physiopathology ; Receptors, LDL/genetics ; Receptors, LDL/metabolism ; Signal Transduction ; Vascular Remodeling/drug effects ; Ventricular Dysfunction, Left/metabolism ; Ventricular Dysfunction, Left/physiopathology ; Ventricular Dysfunction, Right/metabolism ; Ventricular Dysfunction, Right/physiopathology
    Chemical Substances Apolipoprotein A-I ; CD36 Antigens ; CD36 protein, human ; D-4F peptide ; LDLR protein, human ; Lipoproteins, LDL ; Receptors, LDL ; oxidized low density lipoprotein
    Language English
    Publishing date 2020-01-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2653953-6
    ISSN 2047-9980 ; 2047-9980
    ISSN (online) 2047-9980
    ISSN 2047-9980
    DOI 10.1161/JAHA.119.012063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell-Dependent Endothelial Cell Apoptosis.

    Ruffenach, Grégoire / O'Connor, Ellen / Vaillancourt, Mylène / Hong, Jason / Cao, Nancy / Sarji, Shervin / Moazeni, Shayan / Papesh, Jeremy / Grijalva, Victor / Cunningham, Christine M / Shu, Le / Chattopadhyay, Arnab / Tiwari, Shuchita / Mercier, Olaf / Perros, Frédéric / Umar, Soban / Yang, Xia / Gomes, Aldrin V / Fogelman, Alan M /
    Reddy, Srinivasa T / Eghbali, Mansoureh

    Hypertension (Dallas, Tex. : 1979)

    2020  Volume 76, Issue 3, Page(s) 985–996

    Abstract: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated ... ...

    Abstract Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/immunology ; Cell Differentiation ; Cell Proliferation ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Hydroxyeicosatetraenoic Acids/metabolism ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/prevention & control ; Immunologic Factors/pharmacology ; Immunoproteins ; Lipid Metabolism/drug effects ; Mice ; Peptides/pharmacology ; Proteasome Endopeptidase Complex ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; T-Lymphocytes
    Chemical Substances 6F peptide ; Hydroxyeicosatetraenoic Acids ; Immunologic Factors ; Immunoproteins ; Peptides ; 15-hydroxy-5,8,11,13-eicosatetraenoic acid (73945-47-8) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2020-07-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 423736-5
    ISSN 1524-4563 ; 0194-911X ; 0362-4323
    ISSN (online) 1524-4563
    ISSN 0194-911X ; 0362-4323
    DOI 10.1161/HYPERTENSIONAHA.120.14697
    Database MEDical Literature Analysis and Retrieval System OnLINE

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