Role of mutation and pharmacologic block of human KCNH2 in vasculogenesis and fetal mortality: partial rescue by transforming growth factor-ß.
Circ Arrhythm Electrophysiol
; 8(2): 420-8, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25648353
ABSTRACT
BACKGROUND:
N629D KCNH2 is a human missense long-QT2 mutation. Previously, we reported that the N629D/N629D mutation embryos disrupted cardiac looping, right ventricle development, and ablated IKr activity at E9.5. The present study evaluates the role of KCNH2 in vasculogenesis. METHODS ANDRESULTS:
N629D/N629D yolk sac vessels and aorta consist of sinusoids without normal arborization. Isolated E9.5 +/+ first branchial arches showed normal outgrowth of mouse ERG-positive/α-smooth muscle actin coimmunolocalized cells; however, outgrowth was grossly reduced in N629D/N629D. N629D/N629D aortas showed fewer α-smooth muscle actin positive cells that were not coimmunolocalized with mouse ERG cells. Transforming growth factor-ß treatment of isolated N629D/N629D embryoid bodies partially rescued this phenotype. Cultured N629D/N629D embryos recapitulate the same cardiovascular phenotypes as seen in vivo. Transforming growth factor-ß treatment significantly rescued these embryonic phenotypes. Both in vivo and in vitro, dofetilide treatment, over a narrow window of time, entirely recapitulated the N629D/N629D fetal phenotypes. Exogenous transforming growth factor-ß treatment also rescued the dofetilide-induced phenotype toward normal.CONCLUSIONS:
Loss of function of KCNH2 mutations results in defects in cardiogenesis and vasculogenesis. Because many medications inadvertently block the KCNH2 potassium current, these novel findings seem to have clinical relevance.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Fenetilaminas
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Sulfonamidas
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Anormalidades Induzidas por Medicamentos
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Fator de Crescimento Transformador beta
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Neovascularização Fisiológica
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Mutação de Sentido Incorreto
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Bloqueadores dos Canais de Potássio
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Canais de Potássio Éter-A-Go-Go
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Células-Tronco Embrionárias
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Malformações Vasculares
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article