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J. Cardiovasc. Dev. Dis., Volume 2, Issue 3 (September 2015) – 7 articles , Pages 141-247

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1352 KiB  
Article
MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions
by Damien Duval, Pauline Labbé, Léa Bureau, Thierry Le Tourneau, Russell A. Norris, Roger R. Markwald, Robert Levine, Jean-Jacques Schott and Jean Mérot
J. Cardiovasc. Dev. Dis. 2015, 2(3), 233-247; https://doi.org/10.3390/jcdd2030233 - 08 Sep 2015
Cited by 20 | Viewed by 4956
Abstract
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the [...] Read more.
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1–8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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5805 KiB  
Article
Dynamic Heterogeneity of the Heart Valve Interstitial Cell Population in Mitral Valve Health and Disease
by Tori E. Horne, Matthew VandeKopple, Kimberly Sauls, Sara N. Koenig, Lindsey J. Anstine, Vidu Garg, Russell A. Norris and Joy Lincoln
J. Cardiovasc. Dev. Dis. 2015, 2(3), 214-232; https://doi.org/10.3390/jcdd2030214 - 17 Aug 2015
Cited by 26 | Viewed by 6926
Abstract
The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are [...] Read more.
The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are detrimental to biomechanical function and associated with disease. This pathological process is associated with activation of resident VICs that in the absence of disease reside as quiescent cells. While these paradigms have been long standing, characterization of this abundant and ever-changing valve cell population is incomplete. Here we examine the expression pattern of Smooth muscle α-actin, Periostin, Twist1 and Vimentin in cultured VICs, heart valves from healthy embryonic, postnatal and adult mice, as well as mature valves from human patients and established mouse models of disease. We show that the VIC population is highly heterogeneous and phenotypes are dependent on age, species, location, and disease state. Furthermore, we identify phenotypic diversity across common models of mitral valve disease. These studies significantly contribute to characterizing the VIC population in health and disease and provide insights into the cellular dynamics that maintain valve structure in healthy adults and mediate pathologic remodeling in disease states. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Article
Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease
by Kimberly Sauls, Katelynn Toomer, Katherine Williams, Amanda J. Johnson, Roger R. Markwald, Zoltan Hajdu and Russell A. Norris
J. Cardiovasc. Dev. Dis. 2015, 2(3), 200-213; https://doi.org/10.3390/jcdd2030200 - 24 Jul 2015
Cited by 26 | Viewed by 5393
Abstract
Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve [...] Read more.
Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve gestation. Mice deficient in Filamin-A exhibit enlarged mitral leaflets at E17.5, and subsequent progression to a myxomatous phenotype is observed by two months. For this study, we sought to define mechanisms that contribute to myxomatous degeneration in the adult Filamin-A-deficient mouse. In vivo experiments demonstrate increased infiltration of hematopoietic-derived cells and macrophages in adolescent Filamin-A conditional knockout mice. Concurrent with this infiltration of hematopoietic cells, we show an increase in Erk activity, which localizes to regions of MMP2 expression. Additionally, increases in cell proliferation are observed at two months, when hematopoietic cell engraftment and signaling are pronounced. Similar changes are observed in human myxomatous mitral valve tissue, suggesting that infiltration of hematopoietic-derived cells and/or increased Erk signaling may contribute to myxomatous valvular dystrophy. Consequently, immune cell targeting and/or suppression of pErk activities may represent an effective therapeutic option for mitral valve prolapse patients. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Article
Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome
by Robert B. Hinton, Amy M. Opoka, Obah A. Ojarikre, Lawrence S. Wilkinson and William Davies
J. Cardiovasc. Dev. Dis. 2015, 2(3), 190-199; https://doi.org/10.3390/jcdd2030190 - 10 Jul 2015
Cited by 7 | Viewed by 5174
Abstract
Turner syndrome (TS), most frequently caused by X-monosomy (45,X), is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV). There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM) organization and morphometrics [...] Read more.
Turner syndrome (TS), most frequently caused by X-monosomy (45,X), is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV). There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM) organization and morphometrics of the aortic valve and proximal aorta were examined in adult 39,XO mice (where the parental origin of the single X was paternal (39,XPO) or maternal (39,XMO)) and 40,XX controls. Aortic valve morphology was normal (tricuspid) in all of the 39,XPO and 40,XX mice studied, but abnormal (bicuspid or quadricuspid) in 15% of 39,XMO mice. Smooth muscle cell orientation in the ascending aorta was abnormal in all 39,XPO and 39,XMO mice examined, but smooth muscle actin was decreased in 39,XMO mice only. Aortic dilation was present with reduced penetrance in 39,XO mice. The 39,XO mouse demonstrates aortopathy and an X-linked parent-of-origin effect on aortic valve malformation, and the candidate gene FAM9B is polymorphically expressed in control and diseased human aortic valves. The 39,XO mouse model may be valuable for examining the mechanisms underlying the cardiovascular findings in TS, and suggest there are important genetic modifiers on the X chromosome that modulate risk for nonsyndromic BAV and aortopathy. Full article
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Article
Investigation of the Matrix Metalloproteinase-2 Gene in Patients with Non-Syndromic Mitral Valve Prolapse
by Maëlle Perrocheau, Soto Romuald Kiando, Déwi Vernerey, Christian Dina, Pilar Galan, Albert Hagege, Xavier Jeunemaitre and Nabila Bouatia-Naji
J. Cardiovasc. Dev. Dis. 2015, 2(3), 176-189; https://doi.org/10.3390/jcdd2030176 - 10 Jul 2015
Cited by 4 | Viewed by 5006
Abstract
Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate [...] Read more.
Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate etiological mechanism is a perturbation of the extracellular matrix (ECM) remodeling of the valve. To test this hypothesis, we assessed the role of genetic variants in the matrix metalloproteinase 2 gene (MMP2) known to regulate the ECM turnover by direct degradation of proteins and for which transgenic mice develop MVP. Direct sequencing of exons of MMP2 in 47 unrelated patients and segregation analyses in families did not reveal any causative mutation. We studied eight common single nucleotide polymorphisms (TagSNPs), which summarize the genetic information at the MMP2 locus. The association study in two case controls sets (NCases = 1073 and NControls = 1635) provided suggestive evidence for the association of rs1556888 located downstream MMP2 with the risk of MVP, especially in patients with the fibroelastic defiency form. Our study does not support the contribution of MMP2 rare variation in the etiology to MVP in humans, though further genetic and molecular investigation is required to confirm our current suggestive association of one common variant. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Review
Imaging of Mitral Valve Prolapse: What Can We Learn from Imaging about the Mechanism of the Disease?
by Ronen Durst and Dan Gilon
J. Cardiovasc. Dev. Dis. 2015, 2(3), 165-175; https://doi.org/10.3390/jcdd2030165 - 10 Jul 2015
Cited by 6 | Viewed by 6056
Abstract
Mitral valve prolapse (MVP) is the most common mitral valve disorder affecting 2%–3% of the general population. Two histological forms for the disease exist: Myxomatous degeneration and fibroelastic disease. Pathological evidence suggests the disease is not confined solely to the valve tissue, and [...] Read more.
Mitral valve prolapse (MVP) is the most common mitral valve disorder affecting 2%–3% of the general population. Two histological forms for the disease exist: Myxomatous degeneration and fibroelastic disease. Pathological evidence suggests the disease is not confined solely to the valve tissue, and accumulation of proteoglycans and fibrotic tissue can be seen in the adjacent myocardium of MVP patients. MVP is diagnosed by demonstrating valve tissue passing the annular line into the left atrium during systole. In this review we will discuss the advantages and limitations of various imaging modalities in their MVP diagnosis ability as well as the potential for demonstrating extra associated valvular pathologies. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Review
Vascular Calcification and Stone Disease: A New Look towards the Mechanism
by Allen J. Yiu, Daniel Callaghan, Razia Sultana and Bidhan C. Bandyopadhyay
J. Cardiovasc. Dev. Dis. 2015, 2(3), 141-164; https://doi.org/10.3390/jcdd2030141 - 25 Jun 2015
Cited by 27 | Viewed by 7780
Abstract
Calcium phosphate (CaP) crystals are formed in pathological calcification as well as during stone formation. Although there are several theories as to how these crystals can develop through the combined interactions of biochemical and biophysical factors, the exact mechanism of such mineralization is [...] Read more.
Calcium phosphate (CaP) crystals are formed in pathological calcification as well as during stone formation. Although there are several theories as to how these crystals can develop through the combined interactions of biochemical and biophysical factors, the exact mechanism of such mineralization is largely unknown. Based on the published scientific literature, we found that common factors can link the initial stages of stone formation and calcification in anatomically distal tissues and organs. For example, changes to the spatiotemporal conditions of the fluid flow in tubular structures may provide initial condition(s) for CaP crystal generation needed for stone formation. Additionally, recent evidence has provided a meaningful association between the active participation of proteins and transcription factors found in the bone forming (ossification) mechanism that are also involved in the early stages of kidney stone formation and arterial calcification. Our review will focus on three topics of discussion (physiological influences—calcium and phosphate concentration—and similarities to ossification, or bone formation) that may elucidate some commonality in the mechanisms of stone formation and calcification, and pave the way towards opening new avenues for further research. Full article
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