Cardiovascular abnormalities in <i>Folr1</i> knockout mice and folate rescue

Zhu, Huiping; Wlodarczyk, Bogdan J.; Scott, M. Katie; Yu, Wei; Merriweather, Michelle; Waes, Janée Gelineau Van; Schwartz, Robert J.; Finnell, Richard H.

doi:10.1002/bdra.20347

Cited by 52 publications

(44 citation statements)

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“…24 Thus, further studies will be of interest to determine whether genetic variation in Folh1 is contributing to effects on folate metabolism and blood pressure in the SHR compared with the SHR.BN-chr.1 congenic strain. Knockout of Folr1 in the mouse is embryonically lethal, 25 and the effects of genetic variation in Folr1 expression on blood pressure and metabolic traits in mice remain to be determined. Partially rescued preterm Folr1 −/− fetuses were found to have outflow tract defects, aortic arch abnormalities, and isolated dextrocardia.…”

Section: Discussionmentioning

confidence: 99%

“…Partially rescued preterm Folr1 −/− fetuses were found to have outflow tract defects, aortic arch abnormalities, and isolated dextrocardia. 25 To the best of our knowledge, no metabolic traits were studied in these mice.Although the exact relevance of folate metabolism in the SHR model to pathogenesis of metabolic syndrome in humans requires additional study, several lines of evidence strongly suggest that folate deficiency plays a role in at least some features of metabolic syndrome in humans. There is epidemiological evidence showing decreased folate levels or low folate intake to be associated with increased risk of cardiovascular disease and hypertension in humans.…”

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confidence: 99%

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Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

et al. 2016

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Metabolic syndrome is a cluster of clinical disturbances (abdominal obesity, hypertension, dyslipidemia, and impaired glucose tolerance/insulin resistance) associated with an increased risk for diabetes mellitus and cardiovascular disease. Mild hyperhomocysteinemia, a common finding in patients with arteriosclerosis, has been described as a possible component of metabolic syndrome.1,2 Because folates and B vitamins modulate metabolism of homocysteine and of other sulfur amino acids (eg, cysteine, methionine, and cystathionine), mild hyperhomocysteinemia may be mediated by nutritional or genetically determined deficiencies of these vitamins. There is a growing body of epidemiological and clinical evidence for an important role of folate deficiency in human metabolic disturbances and hypertension. [3][4][5] We have shown previously that nutritional folate deficiency leads to development of features of the metabolic syndrome in the spontaneously hypertensive rat (SHR), 6 a widely studied model of essential hypertension associated with increased risk for insulin resistance and dyslipidemia. In this study, in the BXH/HXB recombinant inbred (RI) strains derived from the SHR strain and the normotensive Brown Norway (BN) strain, 7 we used a combination of linkage and correlational analyses of physiological traits and gene expression levels to investigate genetic factors influencing folate and sulfur amino acid metabolism and risk for multiple features of the metabolic syndrome. Methods AnimalsSHR/OlaIpcv rats (referred to as the SHR strain), BN-Lx/Cub rats (referred to as the BN strain), BXH/HXB RI strains 7 derived from the SHR and BN progenitor strains, SHR.BN-D1Mit3/Igf2 congenic Abstract-Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

et al. 2016

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“…It would not be surprising to learn that folate could modulate gene expression also via association with a nuclear form of the folate receptor. [20][21][22][23] Several lines of evidence suggest that the high-affinity folate receptor may contribute to the malignant phenotype. 24 First, the known biologic function of the folate receptor is to supply folates for the biosynthesis of nucleotide bases and the methylation of isoprenylated proteins such as ras.…”

Section: Discussionmentioning

confidence: 99%

Folate receptor overexpression is associated with poor outcome in breast cancer

Hartmann

Keeney

Lingle

et al. 2007

Intl Journal of Cancer

222

136

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The high affinity folate receptor is a membrane-associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty-three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n 5 42) or strong (n 5 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor-targeted approaches in the management of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: folate receptor; breast cancer; prognosis Folic acid and its reduced congeners are required for one carbon transfer reactions that are used in the biosynthesis of nucleotide bases, amino acids and other methylated compounds, and consequently, they are needed in larger quantities by proliferating cells. Physiological folates are transported into cells by either a low affinity reduced folate carrier (K m 5 10 25 M) or a high affinity folate receptor (K d 5 10 210 M). [1][2][3][4][5] The reduced folate carrier is ubiquitously expressed and constitutes the sole folate uptake pathway for most normal cells.The high affinity receptor is a glycosylphosphatidylinositolanchored membrane protein originally identified as a mAb-defined antigen in placenta and trophoblastic cells. It is rarely expressed or inaccessible in most normal cells. However, it is upregulated in select cancers of epithelial origin. 6 Distribution and binding studies of the high affinity folate receptor have shown high expression in the majority of ovarian cancers, and lesser degrees of positivity in kidney, breast, uterine and lung cancers. 6-10 Studies in ovarian cancer have shown an association between folate receptor overexpression and tumor aggressiveness. 7,[11][12][13] Studies of folate receptor expression in breast cancers have found varying results, depending on the techniques used and tissues analyzed. Ross et al. measured mRNA for the folate receptor and found levels to be elevated in five cancers when compared with normal breast specimens; however, the degree of elevation was 10-fold less than that seen in ovarian cancer. 10 Garin-Chesa et al. used a mouse monoclonal antibody LK26 to assess folate receptor expression in a variet...

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“…Results from another of the laboratories collaborating in this study showed multiple developmental abnormalities related to the massive die-off of neural tube and neural crest cells in Folbp1À/À (Folr1À/À) knockout mouse (Piedrahita et al, 1999;Zhu et al, 2007), damage that was far more extensive than is the case for the current study. These contrasting results demonstrate a difference between the global loss of Folbp1 and its reduced expression in a highly focused spatiotemporal manner.…”

Section: Discussionmentioning

confidence: 48%

“…Recent evidence reported by members of this research team indicate that abnormal expression of folate receptor genes in the mouse embryo model is associated with abnormal development of the heart and other neural tube-or neural crest-derived structures (Zhu et al, 2007;Taparia et al, 2007). Furthermore, Saitsu et al (2003) demonstrated that the expression of the folate receptor Folbp1 (also called Folr1, which is homologous with human Folr1 [FRalpha] and avian Folr1) was expressed at high levels in the dorsal neural tube during neural crest formation, indicating its potential role in neural crest development.…”

Section: Introductionmentioning

confidence: 99%

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

Rosenquist

Chaudoin

Finnell

et al. 2010

Developmental Dynamics

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Folate supplementation reduces the incidence of congenital heart defects, but the nature of this protective mechanism remains unclear. Immunolabeling demonstrated that the neural tube and neural crest (NC) cells were rich in the high-affinity folate receptor FOLR1and during the early stages of development FOLR1 was found principally in these cells. Suppression of Folr1 expression in the nascent cardiac NC by site-directed short-interfering RNA (siRNA) altered cardiac NC cell mitosis and subsequent migration patterns leading to abnormal development of the pharyngeal arch arteries (PAA) and outflow tract. qPCR analysis demonstrated that the siRNA treatment significantly reduced Folr1 24 hr after treatment. These treatments also significantly reduced mitosis in the neural tube, but adjacent, nontreated areas were unaffected. In summary, a brief reduction in the expression of Folr1 during a critical stage of NC development had long-term consequences for the development of the PAA and outflow tract. Developmental Dynamics 239:1136-1144,

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Cardiovascular abnormalities in Folr1 knockout mice and folate rescue

Abstract: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field.

Cited by 52 publications

References 74 publications

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

Folate receptor overexpression is associated with poor outcome in breast cancer

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

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