Role of DNA methyltransferase 1 on the altered eNOS expression in human umbilical endothelium from intrauterine growth restricted fetuses
Role of DNA methyltransferase 1 on the altered eNOS expression in human umbilical endothelium from intrauterine growth restricted fetuses
Reduced fetal growth associates with endothelial dysfunction and cardiovascular risk in both young and adult offspring and the nitric oxide (NO) system has been implicated in these effects. Epigenetic processes are likely to underlie such effects, but there is to date no evidence that endothelial dysfunction in early life results from epigenetic processes on key genes in the NO system, such as NOS3 (eNOS) and ARG2 (arginase-2). We determined basal DNA methylation status in NOS3 and ARG2 promoters, and DNA methyltransferase 1 (DNMT1) effect on eNOS and arginase-2 expression using human endothelial cells isolated from umbilical arteries (HUAEC) and veins (HUVEC) from control and intrauterine growth restricted (IUGR) fetuses. Compared with cells from control pregnancies, eNOS protein and mRNA levels were increased in HUAEC, but decreased in HUVEC, from IUGR, while arginase-2 levels were increased in IUGR-HUVEC. The NOS3 promoter showed a decrease in DNA methylation at CpG -352 in IUGR-HUAEC, and an increase in IUGR-HUVEC, when compared with control cells. Methylation in the hypoxia response element of the NOS3 promoter was increased in IUGR-HUAEC and decreased in HUVEC. Methylation in the AGR2 promoter in IUGR-HUVEC was decreased in a putative HRE, and without changes in IUGR-HUAEC. Silencing of DNMT1 expression normalized eNOS expression in IUGR endothelial cells, and restored the normal response to hypoxia in HUVEC, without effects on arginase-2. This data suggest that eNOS expression in IUGR-derived endothelial cells is programmed by altered DNA methylation, and can be reversed by transient silencing of the DNA methylation machinery.
DNA methylation, NOS3, arginase-2, eNOS, fetal programming, human endothelial cells, intrauterine growth restriction
944-952
Krause, B.
6cdc78dd-a984-42ac-b38a-c70853aa273c
Costello, P.M.
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Munoz-Urrutia, E.
d28f051b-c8e8-4608-b038-07b253221002
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Hanson, Mark A.
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Casanello, P.
e6103c63-fad3-46a0-a9cb-639db95cb14a
September 2013
Krause, B.
6cdc78dd-a984-42ac-b38a-c70853aa273c
Costello, P.M.
8fc5c643-2d38-4443-975a-8704af2fa755
Munoz-Urrutia, E.
d28f051b-c8e8-4608-b038-07b253221002
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Hanson, Mark A.
1952fad1-abc7-4284-a0bc-a7eb31f70a3f
Casanello, P.
e6103c63-fad3-46a0-a9cb-639db95cb14a
Krause, B., Costello, P.M., Munoz-Urrutia, E., Lillycrop, Karen A., Hanson, Mark A. and Casanello, P.
(2013)
Role of DNA methyltransferase 1 on the altered eNOS expression in human umbilical endothelium from intrauterine growth restricted fetuses.
Epigenetics, 8 (9), .
(doi:10.4161/epi.25579).
(PMID:23867713)
Abstract
Reduced fetal growth associates with endothelial dysfunction and cardiovascular risk in both young and adult offspring and the nitric oxide (NO) system has been implicated in these effects. Epigenetic processes are likely to underlie such effects, but there is to date no evidence that endothelial dysfunction in early life results from epigenetic processes on key genes in the NO system, such as NOS3 (eNOS) and ARG2 (arginase-2). We determined basal DNA methylation status in NOS3 and ARG2 promoters, and DNA methyltransferase 1 (DNMT1) effect on eNOS and arginase-2 expression using human endothelial cells isolated from umbilical arteries (HUAEC) and veins (HUVEC) from control and intrauterine growth restricted (IUGR) fetuses. Compared with cells from control pregnancies, eNOS protein and mRNA levels were increased in HUAEC, but decreased in HUVEC, from IUGR, while arginase-2 levels were increased in IUGR-HUVEC. The NOS3 promoter showed a decrease in DNA methylation at CpG -352 in IUGR-HUAEC, and an increase in IUGR-HUVEC, when compared with control cells. Methylation in the hypoxia response element of the NOS3 promoter was increased in IUGR-HUAEC and decreased in HUVEC. Methylation in the AGR2 promoter in IUGR-HUVEC was decreased in a putative HRE, and without changes in IUGR-HUAEC. Silencing of DNMT1 expression normalized eNOS expression in IUGR endothelial cells, and restored the normal response to hypoxia in HUVEC, without effects on arginase-2. This data suggest that eNOS expression in IUGR-derived endothelial cells is programmed by altered DNA methylation, and can be reversed by transient silencing of the DNA methylation machinery.
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e-pub ahead of print date: 18 July 2013
Published date: September 2013
Keywords:
DNA methylation, NOS3, arginase-2, eNOS, fetal programming, human endothelial cells, intrauterine growth restriction
Organisations:
Human Development & Health
Identifiers
Local EPrints ID: 367308
URI: http://eprints.soton.ac.uk/id/eprint/367308
ISSN: 1559-2294
PURE UUID: 6785021e-8c83-459c-b908-fc6806dd2817
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Date deposited: 26 Aug 2014 10:33
Last modified: 15 Mar 2024 03:07
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Author:
B. Krause
Author:
P.M. Costello
Author:
E. Munoz-Urrutia
Author:
P. Casanello
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