Impaired Development of Left Anterior Heart Field by Ectopic Retinoic Acid Causes Transposition of the Great Arteries

Narematsu, Mayu; Kamimura, Tatsuya; Yamagishi, Toshiyuki; Fukui, Manabu; Nakajima, Yuji

doi:10.1161/jaha.115.001889

Cited by 11 publications

(8 citation statements)

References 44 publications

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“…RA signaling influences the posterior segment of the heart tube (blue) to establish the primitive atrium and sinus venosus. For example, abnormal development of the cranial anterior SHF by local administration of RA to the second pharyngeal arches in stage 12 chick embryos (corresponding to E8.5 in mouse, Carnegie stage 10 in human) causes TGA (Narematsu, Kamimura, Yamagishi, Fukui, & Nakajima, 2015); and ablation of the caudal anterior SHF in the posterior pharyngeal arches at stage 14 (E9.0 in mouse, Carnegie stage 11 in human) causes TOF . (a) The SHF is subdivided into posterior and anterior SHFs.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid signaling in heart development

Nakajima

2019

Genesis

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Summary Retinoic acid (RA) is a vitamin A metabolite that acts as a morphogen and teratogen. Excess or defective RA signaling causes developmental defects including in the heart. The heart develops from the anterior lateral plate mesoderm. Cardiogenesis involves successive steps, including formation of the primitive heart tube, cardiac looping, septation, chamber development, coronary vascularization, and completion of the four‐chambered heart. RA is dispensable for primitive heart tube formation. Before looping, RA is required to define the anterior/posterior boundaries of the heart‐forming mesoderm as well as to form the atrium and sinus venosus. In outflow tract elongation and septation, RA signaling is required to maintain/differentiate cardiogenic progenitors in the second heart field at the posterior pharyngeal arches level. Epicardium‐secreted insulin‐like growth factor, the expression of which is regulated by hepatic mesoderm‐derived erythropoietin under the control of RA, promotes myocardial proliferation of the ventricular wall. Epicardium‐derived RA induces the expression of angiogenic factors in the myocardium to form the coronary vasculature. In cardiogenic events at different stages, properly controlled RA signaling is required to establish the functional heart.

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Section: Introductionmentioning

confidence: 99%

Retinoic acid signaling in heart development

Nakajima

2019

Genesis

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“…Retinoic acid (RA), an active metabolite of vitamin A that acts through nuclear retinoid receptors, influences gene expression, alters the synthesis of proteins in the heart, and regulates embryonic development, tissue homeostasis, and cellular differentiation and proliferation [1-3]. …”

Section: Introductionmentioning

confidence: 99%

Cardiac Remodeling Induced by All-Trans Retinoic Acid is Detrimental in Normal Rats

Silva¹,

Gonçalves²,

Santos³

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study aimed to discern whether the cardiac alterations caused by retinoic acid (RA) in normal adult rats are physiologic or pathologic. Methods and Results: Wistar rats were assigned into four groups: control animals (C, n = 20) received a standard rat chow; animals fed a diet supplemented with 0.3 mg/kg/day all-trans-RA (AR1, n = 20); animals fed a diet supplemented with 5 mg/kg/day all-trans-RA (AR2, n = 20); and animals fed a diet supplemented with 10 mg/kg/day all-trans-RA (AR3, n = 20). After 2 months, the animals were submitted to echocardiogram, isolated heart study, histology, energy metabolism status, oxidative stress condition, and the signaling pathway involved in the cardiac remodeling induced by RA. RA increased myocyte cross-sectional area in a dose-dependent manner. The treatment did not change the morphological and functional variables, assessed by echocardiogram and isolated heart study. In contrast, RA changed catalases, superoxide dismutase, and glutathione peroxidases and was associated with increased values of lipid hydroperoxide, suggesting oxidative stress. RA also reduced citrate synthase, enzymatic mitochondrial complex II, ATP synthase, and enzymes of fatty acid metabolism and was associated with increased enzymes involved in glucose use. In addition, RA increased JNK 1/2 expression, without changes in TGF-β, PI3K, AKT, NFκB, S6K, and ERK. Conclusion: In normal rats, RA induces cardiac hypertrophy in a dose-dependent manner. The non-participation of the PI3K/Akt pathway, associated with the participation of the JNK pathway, oxidative stress, and changes in energy metabolism, suggests that cardiac remodeling induced by RA supplementation is deleterious.

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“…), suggesting potential regions responsible for specific conotruncal heart defects (Nakajima ). Indeed, laser ablation of the right SHF caused tetralogy of Fallot (TOF) (Ward et al ), and an impaired development of the left AHF by locally administrated retinoic acid, having a teratogenic effect to OFT development in human and laboratory animals, caused TGA morphology in chick embryonic heart (Narematsu et al ).…”

Section: Introductionmentioning

confidence: 99%

“…This consideration is consistent with the results from a time‐controlled deletion of Tbx1 (Xu et al ). In avian embryos, retinoic acid‐induced perturbation of AHF and laser ablation of SHF caused TGA and TOF, respectively (Ward et al ; Narematsu et al ). Taken together, it may be suggested that Tbx1 mainly functions in the SHF, which is located in the posterior (caudal) pharyngeal arches after the completion of the right ventricle and proximal OFT from the AHF.…”

Section: Introductionmentioning

confidence: 99%

Mechanism responsible for D‐transposition of the great arteries: Is this part of the spectrum of right isomerism?

Nakajima

2016

Congenital Anomalies

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D-transposition of the great arteries (TGA) is one of the most common conotruncal heart defects at birth and is characterized by a discordant ventriculoarterial connection with a concordant atrioventricular connection. The morphological etiology of TGA is an inverted or arrested rotation of the heart outflow tract (OFT, conotruncus), by which the aorta is transposed in the right ventral direction to the pulmonary trunk. The rotational defect of the OFT is thought to be attributed to hypoplasia of the subpulmonic conus, which originates from the left anterior heart field (AHF) residing in the mesodermal core of the first and second pharyngeal arches. AHF, especially on the left, at the early looped heart stage (corresponding to Carnegie stage 10-11 in the human embryo) is one of the regions responsible for the impediment that causes TGA morphology. In human or experimentally produced right isomerism, malposition of the great arteries including D-TGA is frequently associated. Mutations in genes involving left-right (L-R) asymmetry, such as NODAL, ACTRIIB and downstream target FOXH1, have been found in patients with right isomerism as well as in isolated TGA. The downstream pathways of Nodal-Foxh1 play a critical role not only in L-R determination in the lateral plate mesoderm but also in myocardial specification and differentiation in the AHF, suggesting that TGA is a phenotype in heterotaxia as well as the primary developmental defect of the AHF.

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Impaired Development of Left Anterior Heart Field by Ectopic Retinoic Acid Causes Transposition of the Great Arteries

Cited by 11 publications

References 44 publications

Retinoic acid signaling in heart development

Retinoic acid signaling in heart development

Cardiac Remodeling Induced by All-Trans Retinoic Acid is Detrimental in Normal Rats

Mechanism responsible for D‐transposition of the great arteries: Is this part of the spectrum of right isomerism?

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