GWAS-driven Pathway Analyses and Functional Validation Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse

AbstractNonsyndromic Mitral valve prolapse (MVP) is a common degenerative valvular heart disease with severe health consequences, including arrhythmia, heart failure and sudden death. MVP is characterized by excess extracellular matrix secretion and cellular disorganization which leads to bulky valves that are unable to co-apt properly during ventricular systole. However, the triggering mechanisms of this process are mostly unknown. Using pathway enrichment tools applied to GWAS we show that genes at risk loci are involved in biological functions relevant to cell adhesion and migration during cardiac development and in response to shear stress. Through genetic, in silico and in vivo experiments we demonstrates the presence of several genes involved in gene regulation, including GLIS1, a transcription factor that regulates Hedgehog signaling. Our findings define genetic, molecular and cellular mechanisms underlying non-syndromic MVP and implicate disrupted endothelial to mesenchymal transition and cell migration as a potential common cause to this disease.

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GWAS-driven Pathway Analyses and Functional Validation Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse

Structural Heart ◽

10.1080/24748706.2019.1587946 ◽

2019 ◽

Vol 3 (sup1) ◽

pp. 108-108

Author(s):

Mengyao Yu ◽

Adrien Georges ◽

Nathan R. Tucker ◽

Sergiy Kyryachenko ◽

Patrick T. Ellinor ◽

...

Keyword(s):

Mitral Valve ◽

Mitral Valve Prolapse ◽

Susceptibility Gene ◽

Functional Validation ◽

Pathway Analyses

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MicroRNAs in Valvular Heart Diseases: Biological Regulators, Prognostic Markers and Therapeutical Targets

International Journal of Molecular Sciences ◽

10.3390/ijms222212132 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12132

Author(s):

Francesco Nappi ◽

Adelaide Iervolino ◽

Sanjeet Singh Avtaar Singh ◽

Massimo Chello

Keyword(s):

Mitral Valve ◽

Mitral Valve Prolapse ◽

Heart Diseases ◽

Osteoblastic Differentiation ◽

New Drugs ◽

Expression Vectors ◽

Chordae Tendineae ◽

Valvular Heart Diseases

miRNAs have recently attracted investigators’ interest as regulators of valvular diseases pathogenesis, diagnostic biomarkers, and therapeutical targets. Evidence from in-vivo and in-vitro studies demonstrated stimulatory or inhibitory roles in mitral valve prolapse development, aortic leaflet fusion, and calcification pathways, specifically osteoblastic differentiation and transcription factors modulation. Tissue expression assessment and comparison between physiological and pathological phenotypes of different disease entities, including mitral valve prolapse and mitral chordae tendineae rupture, emerged as the best strategies to address miRNAs over or under-representation and thus, their impact on pathogeneses. In this review, we discuss the fundamental intra- and intercellular signals regulated by miRNAs leading to defects in mitral and aortic valves, congenital heart diseases, and the possible therapeutic strategies targeting them. These miRNAs inhibitors are comprised of antisense oligonucleotides and sponge vectors. The miRNA mimics, miRNA expression vectors, and small molecules are instead possible practical strategies to increase specific miRNA activity. Advantages and technical limitations of these new drugs, including instability and complex pharmacokinetics, are also presented. Novel delivery strategies, such as nanoparticles and liposomes, are described to improve knowledge on future personalized treatment directions.

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Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits chemical-induced skin cancer through suppressing hedgehog signaling

Experimental Biology and Medicine ◽

10.1177/1535370219897240 ◽

2020 ◽

Vol 245 (3) ◽

pp. 213-220

Author(s):

Dianhui Xiu ◽

Min Cheng ◽

Wenlei Zhang ◽

Xibo Ma ◽

Lin Liu

Keyword(s):

Pseudomonas Aeruginosa ◽

Skin Cancer ◽

Hedgehog Signaling ◽

Anticancer Agent ◽

Epithelial Mesenchymal Transition ◽

Cell Counting ◽

Mesenchymal Transition ◽

Anticancer Properties

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PAM) is an inactivate P. aeruginosa with mannose-sensitive hemagglutinin. Recently, the anticancer properties of PAM against many cancers have been reported across a range of studies. However, the exact mechanism through which PAM prevents skin cancer remains unclear. The aim of this study is to show to what extent PAM could inhibit the dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin cancer. JB6 cells were treated by TPA so as to establish an in vitro model. The effects of PAM on proliferation of the cells were analyzed using cell counting kit-8 assays. Effects on epithelial–mesenchymal transition (EMT) were assayed by real-time PCR and Western blotting. A DMBA/TPA-induced skin cancer mouse model was also established. The results showed that TPA promoted EMT changes through the activation of the hedgehog (Hh) pathway, which was reversed by PAM. Moreover, PAM inhibited the cancer growth and Hh pathway in vivo. These data indicate that PAM may serve as a potential anticancer agent for the treatment of skin cancer. Impact statement Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PAM) restrained the chemical-induced skin cancer cells in vitro and in vivo partly through suppressing the Hh signaling pathway, indicating that PAM may be a promising anticancer agent for treating skin cancer.

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

Circulation Research ◽

10.1161/circresaha.119.316427 ◽

2020 ◽

Vol 127 (3) ◽

Cited By ~ 1

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.

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GWAS-driven pathway analyses and functional studies reveals GLIS1 to predispose to mitral valve prolapse

Archives of Cardiovascular Diseases Supplements ◽

10.1016/s1878-6480(17)30286-0 ◽

2017 ◽

Vol 9 (1) ◽

pp. 96

Author(s):

M. Yu ◽

C. Dina ◽

N. Tucker ◽

F. Delling ◽

S. Slaugenhaupt ◽

...

Keyword(s):

Mitral Valve ◽

Mitral Valve Prolapse ◽

Functional Studies ◽

Pathway Analyses

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Consequences of mitral valve prolapse on chordal tension: Ex vivo and in vivo studies in large animal models

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2011.08.035 ◽

2011 ◽

Vol 142 (6) ◽

pp. 1585-1587 ◽

Cited By ~ 13

Author(s):

Mathieu Granier ◽

Morten O. Jensen ◽

Jesper L. Honge ◽

Alain Bel ◽

Philippe Menasché ◽

...

Keyword(s):

Mitral Valve ◽

Animal Models ◽

Mitral Valve Prolapse ◽

Ex Vivo ◽

In Vivo Studies ◽

Large Animal ◽

Large Animal Models

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Abstract 18584: Filamin-A Mutations Causing Mitral Valve Prolapse Alters Integrin Expression and Causes Breakdown of Mechanotransduction

Circulation ◽

10.1161/circ.130.suppl_2.18584 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Muralidhar Padala ◽

Marzieh H Zamani ◽

Padmini Sarathchandra ◽

Jean Merot ◽

Julia Gorelik ◽

...

Keyword(s):

Mitral Valve ◽

Mitral Valve Prolapse ◽

Cultured Cells ◽

Cell Attachment ◽

Cell Structure ◽

Integrin Expression ◽

Filamin A ◽

Mechanical Stiffness ◽

Cellular Mechanisms ◽

The Impact

Introduction: Mutations in the gene encoding Filamin-A, a cytoskeletal protein, were identified in patients with familial mitral valve prolapse(MVP). Mitral valves in these patients were floppy and appeared myxomatous, but the underlying mechanisms governing such changes are unclear. In this study, we sought to investigate the impact of these mutations on cultured cells in comparison with wild type Filamin-A, to delineate the mechanisms underlying MVP. Methods: Four immortal cell lines were established - Filamin-A KO, Filamin-A WT, G288R mutated Filamin-A, and P637Q mutated Filamin-A. Cells were cultured on plastic petri-dishes for a week, and at confluence the cells were imaged under a microscope, then their 3D morphology and mechanical stiffness measured with scanning ion conductance microscopy, and then the cells were assayed for integrins and counted using flow cytometry. Results: Filamin-A KO cells developed blebs on the surface, were flat and did not sufficiently attach to the cell culture substrate, while WT cells demonstrated excellent attachment and formed extensive lamellapodi and filipodia (Fig 1A). Both G288R and P637Q mutated cells had reduced extensions, with a cell structure that is small in circumference but large in height(Fig 1B). α1, α2, α3, α5, β1, β3, β4, α5β3, α2β1 integrin expression was drastically reduced in both G288R and P637Q mutations, compared to WT (Fig 1C1-C2). A 24 hour substrate attachment assay demonstrated 30% attachment of G288R cells were attached and viable, 50% of the P637Q cells were attached and viable, and 98% of WT cells were attached and viable, with similar results seen in gel contraction studies (Fig 1D). Conclusions: Filamin-A mutations associated with mitral valve prolapse seem to alter fundamental cellular mechanisms essential for cell attachment to matrix, motility and mechanotransduction.

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Cerebral ischemia in young patients: it is associated with mitral valve prolapse and abnormal platelet activity in vivo?

Stroke ◽

10.1161/01.str.13.4.454 ◽

1982 ◽

Vol 13 (4) ◽

pp. 454-458 ◽

Cited By ~ 41

Author(s):

R E Scharf ◽

M Hennerici ◽

V Bluschke ◽

J Lueck ◽

R G Kladetzky

Keyword(s):

Cerebral Ischemia ◽

Mitral Valve ◽

Mitral Valve Prolapse ◽

Young Patients ◽

Platelet Activity

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Biphasic roles of hedgehog signaling in the production and self-renewal of outer radial glia in the ferret cerebral cortex

10.1101/2021.04.12.439562 ◽

2021 ◽

Author(s):

Shirui Hou ◽

Wan-Ling Ho ◽

Lei Wang ◽

Bryan Kuo ◽

Jun Young Park ◽

...

Keyword(s):

Hedgehog Signaling ◽

Radial Glia ◽

Superficial Layer ◽

Cellular Mechanisms ◽

Self Renewal ◽

Layer Neuron ◽

Outer Radial Glia ◽

Hh Signaling ◽

Necessary And Sufficient

The neocortex, the center for higher brain function, emerged in mammals and expanded in the course of evolution. The expansion of outer radial glia (oRGs) and intermediate progenitor cells (IPCs) plays key roles in the expansion and consequential folding of the neocortex. Therefore, understanding the mechanisms of oRG and IPC expansion is important for understanding neocortical development and evolution. By using mice and human cerebral organoids, we previously revealed that hedgehog (HH) signaling expands oRGs and IPCs. Nevertheless, it remained to be determined whether HH signaling expanded oRGs and IPCs in vivo in gyrencephalic species, in which oRGs and IPCs are naturally expanded. Here, we show that HH signaling is necessary and sufficient to expand oRGs and IPCs in ferrets, a gyrencephalic species, through conserved cellular mechanisms. HH signaling increases oRG-producing division modes of ventricular radial glia (vRGs), oRG self-renewal, and IPC proliferation. Notably, HH signaling affects vRG division modes only in an early restricted phase before superficial-layer neuron production peaks. Beyond this restricted phase, HH signaling promotes oRG self-renewal. Thus, HH signaling expands oRGs and IPCs in two distinct but continuous phases during cortical development.

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