scholarly journals A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse

2020 ◽  
Vol 127 (3) ◽  
Author(s):  
Jaime Ibarrola ◽  
Amaia Garcia-Peña ◽  
Lara Matilla ◽  
Benjamin Bonnard ◽  
Rafael Sádaba ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Mineralocorticoid Receptor ◽  
Cell Activation ◽  
Cardiac Fibrosis ◽  
Interstitial Cell ◽  
Activation Markers ◽  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

Rationale: Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. Objective: We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. Methods and Results: Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. Conclusions: These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.

scholarly journals Human myxomatous mitral valve prolapse: Role of bone morphogenetic protein 4 in valvular interstitial cell activation

2012 ◽  
Vol 227 (6) ◽  
pp. 2595-2604 ◽  
Author(s):  
Rachana Sainger ◽  
Juan B. Grau ◽  
Emanuela Branchetti ◽  
Paolo Poggio ◽  
William F. Seefried ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Bone Morphogenetic Protein ◽  
Mitral Valve Prolapse ◽  
Cell Activation ◽  
Interstitial Cell ◽  
Bone Morphogenetic Protein 4 ◽  
Morphogenetic Protein

scholarly journals The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Juan Wang ◽  
Wen He ◽  
Xiao Xu ◽  
Liping Guo ◽  
Yin Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Human Coronary Artery ◽  
Mesenchymal Transition ◽  
Twist Expression ◽  
Endothelial Mesenchymal Transition

Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial–mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.

scholarly journals Mitral valve endothelial cells secrete osteoprotegerin during endothelial mesenchymal transition

2016 ◽  
Vol 98 ◽  
pp. 48-57 ◽  
Author(s):  
Paola Songia ◽  
Emanuela Branchetti ◽  
Alessandro Parolari ◽  
Veronika Myasoedova ◽  
Giovanni Ferrari ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mitral Valve ◽  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

Abstract 222: Dkk1 and Msx2-Wnt7b Signaling Reciprocally Regulate the Endothelial-Mesenchymal Transition in Aortic Endothelial Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Su-Li Cheng ◽  
Jian-su Shao ◽  
Abraham Behrmann ◽  
Karen Krchma ◽  
Dwight A Towler
Keyword(s):  
Endothelial Cells ◽  
Mesenchymal Cell ◽  
Type I ◽  
Cuboidal Cell ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Cell Responses ◽  
The Impact ◽  
Endothelial Mesenchymal Transition ◽  
Aortic Endothelial

Objective Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition (EndMT) during tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic calcification and fibrosis. We studied the impact of Wnt7, Msx2, and Dkk1 (Wnt7 antagonist) on EndMT in primary aortic endothelial cells (AoECs). Methods and Results Transduction of AoECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1 and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibrogenic and osteogenic markers - e.g., SM22, type I collagen, Osx, Runx2, alkaline phosphatase – were upregulated by Dkk1 via activin-like kinase / Smad pathways. Dkk1 increased fibrosis and mineralization of AoECs cultured under osteogenic conditions - the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained the “cobblestone” morphology of differentiated ECs and promoted EC marker expression. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR-/- mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and nuclear pSmad1/5, and increased collagen accumulation. Conclusions Dkk1 enhances EndMT in AoECs, while Msx2-Wnt7 signals stabilize EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal cell responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.

scholarly journals Hemagglutinin-Dependent Tropism of H5N1 Avian Influenza Virus for Human Endothelial Cells

2009 ◽  
Vol 83 (24) ◽  
pp. 12947-12955 ◽  
Author(s):  
Manuela Ocaña-Macchi ◽  
Michael Bel ◽  
Laurence Guzylack-Piriou ◽  
Nicolas Ruggli ◽  
Matthias Liniger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Avian Influenza ◽  
Cell Activation ◽  
De Novo ◽  
Binding Capacity ◽  
Multiorgan Failure ◽  
Influenza Viruses ◽  
Human Influenza ◽  
Receptor Specificity ◽  
Activation Markers

ABSTRACT Although current H5N1 highly pathogenic avian influenza viruses (HPAIV) are inefficiently transmitted to humans, infected individuals can suffer from severe disease, often progressing rapidly to acute respiratory distress syndrome and multiorgan failure. This is in contrast with the situation with human influenza viruses, which in immunocompetent individuals usually cause only a respiratory disease which is less aggressive than that observed with avian H5N1 viruses. While the biological basis of inefficient transmission is well documented, the mechanisms by which the H5N1 viruses cause fatal disease remain unclear. In the present study, we demonstrate that human pulmonary microvascular endothelial cells (hPMEC) had a clearly higher susceptibility to infection by H5N1 HPAIV than to infection by human influenza viruses. This was measurable by de novo intracellular nucleoprotein production and virus replication. It was also related to a relatively higher binding capacity to cellular receptors. After infection of hPMEC, cell activation markers E-selectin and P-selectin were upregulated, and the proinflammatory cytokines interleukin-6 and beta interferon were secreted. H5N1 virus infection was also associated with an elevated rate of cell death. Reverse genetics analyses demonstrated a major role for the viral hemagglutinin in this cell tropism. Overall, avian H5N1 viruses have a particular receptor specificity targeting endothelial cells that is different from human influenza viruses, and this H5N1 receptor specificity could contribute to disease pathogenesis.

scholarly journals Correction to: Matrix metalloproteinase 9 induces endothelial-mesenchymal transition via Notch activation in human kidney glomerular endothelial cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ye Zhao ◽  
Xi Qiao ◽  
Lihua Wang ◽  
Tian Kui Tan ◽  
Hong Zhao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Human Kidney ◽  
Matrix Metalloproteinase 9 ◽  
Mesenchymal Transition ◽  
Glomerular Endothelial Cells ◽  
Metalloproteinase 9 ◽  
Endothelial Mesenchymal Transition ◽  
Notch Activation

An amendment to this paper has been published and can be accessed via the original article.

Transcriptional regulation of endothelial-to-mesenchymal transition in cardiac fibrosis: role of myocardin-related transcription factor A and activating transcription factor 3

2017 ◽  
Vol 95 (10) ◽  
pp. 1263-1270 ◽  
Author(s):  
Vibhuti Sharma ◽  
Nilambra Dogra ◽  
Uma Nahar Saikia ◽  
Madhu Khullar
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Cardiac Fibrosis ◽  
Activating Transcription Factor 3 ◽  
Mesenchymal Transition ◽  
Related Transcription Factor ◽  
Endothelial To Mesenchymal Transition ◽  
Activating Transcription Factor ◽  
Transcription Factor 3

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor β (TGF-β) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-β in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-β ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.

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