Selective regulation of cardiomyocyte gene expression and cardiac morphogenesis by retinoic acid

Dickman, Eileen D.; Smith, Susan

doi:10.1002/(sici)1097-0177(199605)206:1<39::aid-aja4>3.0.co;2-1

Cited by 60 publications

(26 citation statements)

References 37 publications

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“…In regards to apoptosis, there was no evidence of dying cells within the newly formed mesenchyme, myocardium or endothelium suggesting that the decrease in cell number was not due to cell death caused by RA. This is consistent with other investigators, who reported no evidence of cell death using the same concentration of RA (Wiens et al, 1992;Dickman and Smith, 1996). Because we did not specifically test for apoptosis, however, we can not completely rule out this process as contributing to the decrease in mesenchyme cells.…”

Section: Discussionsupporting

confidence: 91%

“…RA may either increase or decrease the differentiation of myocardium (Drysdale et al, 1997;Kastner et al, 1997). Studies have also reported that RA inhibits cardiac myocyte proliferation, development of heart contractions and ␣-actin synthetic rate (Wiens et al, 1992;Dickman and Smith, 1996). Finally, myocardial differentiation markers in Xenopus embryos are blocked upon exposure to RA, whereas the pattern of endocardial gene expression remained unaffected (Drysdale et al, 1997).…”

Section: Discussionmentioning

confidence: 96%

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Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Yan

Sinning

2001

Anat. Rec.

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Retinoic acid has been associated with a number of cardiac defects, some of which seem to be related to changes in the endocardial cushions. Studies in mice and older chick embryos have suggested that these defects may be associated with a decrease in mesenchymal cell formation within the cushion. In a previous report we showed that retinoic acid lowered the number of mesenchymal cells in a culture bioassay of mesenchyme formation and that this response was due to retinoic acid modifying the production of particulate matrix from the myocardium. In this study, we have extended these observations to the embryo by implanting a retinoic acid coated bead into the embryo and examined the effect on cardiac mesenchyme formation and in the production of the particulate matrix. In all cases the addition of retinoic acid resulted in a decrease in the number of mesenchymal cells invading the endocardial cushions. In addition retinoic acid increased the production of hLAMP-1 and fibronectin but not transferrin, confirming our earlier report. Finally, we measured the volume of the cushion and calculated the cell density of both the inferior and superior cushions. The results suggest that the superior cushion is more sensitive to retinoic acid treatment than the inferior cushion. Collectively, these results support our earlier work that suggests that the mechanism of retinoic acid cardiac abnormalities involves a disruption in the production of particulate matrix from the myocardium and a subsequent decrease in cardiac mesenchyme cells that results in a malformed cardiac cushions. Anat Rec 263: [53][54][55][56][57][58][59][60][61] 2001.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Yan

Sinning

2001

Anat. Rec.

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“…The addition of exogenous RA to chick embryo cultures between stages 5 and 8 produces various anomalies, which have initially been described as abnormal precardiac cell migration [63,65]. In fact, Yutzey et al have shown that RA treatment produces an expansion of the atrial domain observed by the expression of the atrial-specific myosin heavy chain AMHC1 [64].…”

Section: Retinoic Acid and Early Heart Developmentmentioning

confidence: 99%

Retinoids and Cardiac Development

Zaffran

Robrini

Bertrand

2014

JDB

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Retinoic acid (RA), a derivative of vitamin A, is involved in signal transduction during vertebrate organogenesis. Retinoids through binding to nuclear receptors called RA receptors (RARs) and retinoid X receptors (RXRs) regulate various processes during cardiogenesis. Deregulated retinoid signaling thus has later consequences leading to cardiac malformations. In this review, we will summarize and discuss our current knowledge on the role of RA signaling during heart development, especially during patterning of the heart fields. We have also integrated recent experiments essential for our understanding of the role of RA signaling during epicardial development and myocardial growth.

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“…No instances of cardia bifida or atrial expansion indicative of high retinoid levels 16 were observed, nor were VAD symptoms, such as sinus venosus obliteration. 17 Rightward looping of the cardiac tube, which is randomized during retinoid excess or absence, 9,18 was also normal.…”

Section: Rbp-null Mice Reveal No Overt Dysmorphologymentioning

confidence: 94%

Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein–Null Mice

Wendler

Schmoldt

Flentke

et al. 2003

Circulation Research

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Abstract-Precise regulation of retinoid levels is critical for normal heart development. Retinol-binding protein (RBP), an extracellular retinol transporter, is strongly secreted by cardiogenic endoderm. This study addresses whether RBP gene ablation affects heart development. Despite exhibiting an Ͼ85% decrease in serum retinol, adult RBP-null mice are viable, breed, and have normal vision when maintained on a vitamin A-sufficient diet. Comparison of RBP-null with wild-type (WT) hearts from embryos at day 9.0 (E9.0) through E12.5 revealed an RBP-null phenotype similar to that of other retinoid-deficient models. At an early stage, RBP-null hearts display retarded trabecular development, which recovers by E9.5. This is accompanied at E9.5 and E10.5 by precocious differentiation of subepicardial cardiac myocytes. Most remarkably, RBP-null hearts display augmented deposition of fibronectin protein in the cardiac jelly at E9.0 through E10.5 and in the outflow tract at E12.5. This phenomenon, which was detected by immunohistochemistry and Western blotting without increased fibronectin transcript levels, is accompanied by increased numbers of mesenchymal cells in the outflow tract but not in the atrioventricular canal. RBP-null cardiac myocytes, especially in the subepicardial layer, display increased cell proliferation. This phenotype may present a model of subclinical retinoid insufficiency characterized by alteration of an extracellular matrix component and altered cellular differentiation and proliferation, changes that may have functional consequences for adult cardiac function. This murine model may have relevance to fetal development in human populations with inadequate retinoid intake. Key Words: retinol-binding protein knockout Ⅲ retinoic acid Ⅲ mouse heart development Ⅲ cardiac jelly Ⅲ fibronectin T he biologically active derivative of vitamin A, retinoic acid (RA), plays an essential role in regulating the homeostasis of adult organs as well as the development of numerous embryonic tissues. Precisely regulated retinoid levels are crucial for normal development of the cardiovascular system: too much or too little RA causes profound cardiac teratogenicity. 1,2 For example, excess RA causes effects ranging from diminished cardiac jelly and outflow tract (OFT) disruption 3,4 to the total and specific absence of the embryonic heart. 5 On the other hand, vitamin A deficiency (VAD) causes aortic arch anomalies, ventricular septal defects, and retarded myocardial development 6 reflecting cellular deficits, including hypoplastic myocardial walls that contain precociously differentiated cardiac myocytes. 7,8 Most deficits caused by VAD are recapitulated by ablation of the genes involved in retinoid synthesis, such as retinaldehydeoxidizing dehydrogenase (RALDH2), 9 or genes in the retinoid signaling pathway, including the RA receptor (RAR) and retinoid X receptor (RXR) genes. 7,8,10,11 These findings suggest that the ablation of genes that regulate retinoid delivery, such as the retinol-binding protein (RBP) gene, m...

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Selective regulation of cardiomyocyte gene expression and cardiac morphogenesis by retinoic acid

Cited by 60 publications

References 37 publications

Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Retinoids and Cardiac Development

Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein–Null Mice

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