High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects
Abstract Congenital heart defects (CHDs) represent one of the most prevalent categories of neonatal defects, and maternal dietary patterns have been linked to the risk of these conditions. Branched‐chain amino acids (BCAAs), particularly leucine, are essential for various metabolic and physiological...
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| Format: | Article |
| Language: | English |
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Wiley
2024-10-01
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| Series: | Pulmonary Circulation |
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| Online Access: | https://doi.org/10.1002/pul2.70013 |
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| author | Wei Hong Guozhou You Zhongming Luo Mingxiang Zhang Jian Chen |
| author_facet | Wei Hong Guozhou You Zhongming Luo Mingxiang Zhang Jian Chen |
| author_sort | Wei Hong |
| collection | DOAJ |
| description | Abstract Congenital heart defects (CHDs) represent one of the most prevalent categories of neonatal defects, and maternal dietary patterns have been linked to the risk of these conditions. Branched‐chain amino acids (BCAAs), particularly leucine, are essential for various metabolic and physiological processes involved in heart development. In this study, we examined the molecular mechanisms through which elevated levels of leucine induce defects in cardiac microvascular endothelial cells. We collected plasma samples from healthy controls and neonatal patients with CHDs, employed a high‐leucine diet for pregnant female mice, and applied high‐leucine treatment in human cardiac microvascular endothelial cells (HCMECs). The impacts of high‐leucine levels on WD Repeat Containing Planar Cell Polarity Effector (WDPCP)/MAPK signaling axis were investigated in the cell and animal models. We reported heightened plasma leucine levels in neonatal patients with CHDs and observed that a high‐leucine diet in pregnant mice was associated with reduced expression of WDPCP and attenuated MAPK/ERK signaling. High‐leucine treatment in HCMECs impaired epithelial‐mesenchymal transition (EMT) and cell migration; however, overexpression of WDPCP or activation of MAPK exhibited a rescue effect. The upregulation of endomucin (EMCN) under high‐leucine conditions contributed to the impaired EMT and migratory capacity of HCMECs, and the WDPCP/MAPK signaling axis regulated EMCN overexpression in response to high‐leucine treatment. High levels of leucine in neonatal patients with CHDs may inhibit the WDPCP/MAPK axis, leading to an increase in EMCN expression that undermines the function of cardiac microvascular endothelial cells. These findings suggest the potential of targeting the WDPCP/MAPK axis as an intervention strategy for neonatal CHDs. |
| format | Article |
| id | doaj-art-699ae1b15414489a9220141743a55302 |
| institution | OA Journals |
| issn | 2045-8940 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj-art-699ae1b15414489a9220141743a553022025-08-20T02:01:04ZengWileyPulmonary Circulation2045-89402024-10-01144n/an/a10.1002/pul2.70013High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defectsWei Hong0Guozhou You1Zhongming Luo2Mingxiang Zhang3Jian Chen4Kunming Children's Hospital Kunming Yunnan ChinaKunming Children's Hospital Kunming Yunnan ChinaKunming Children's Hospital Kunming Yunnan ChinaKunming Children's Hospital Kunming Yunnan ChinaKunming Children's Hospital Kunming Yunnan ChinaAbstract Congenital heart defects (CHDs) represent one of the most prevalent categories of neonatal defects, and maternal dietary patterns have been linked to the risk of these conditions. Branched‐chain amino acids (BCAAs), particularly leucine, are essential for various metabolic and physiological processes involved in heart development. In this study, we examined the molecular mechanisms through which elevated levels of leucine induce defects in cardiac microvascular endothelial cells. We collected plasma samples from healthy controls and neonatal patients with CHDs, employed a high‐leucine diet for pregnant female mice, and applied high‐leucine treatment in human cardiac microvascular endothelial cells (HCMECs). The impacts of high‐leucine levels on WD Repeat Containing Planar Cell Polarity Effector (WDPCP)/MAPK signaling axis were investigated in the cell and animal models. We reported heightened plasma leucine levels in neonatal patients with CHDs and observed that a high‐leucine diet in pregnant mice was associated with reduced expression of WDPCP and attenuated MAPK/ERK signaling. High‐leucine treatment in HCMECs impaired epithelial‐mesenchymal transition (EMT) and cell migration; however, overexpression of WDPCP or activation of MAPK exhibited a rescue effect. The upregulation of endomucin (EMCN) under high‐leucine conditions contributed to the impaired EMT and migratory capacity of HCMECs, and the WDPCP/MAPK signaling axis regulated EMCN overexpression in response to high‐leucine treatment. High levels of leucine in neonatal patients with CHDs may inhibit the WDPCP/MAPK axis, leading to an increase in EMCN expression that undermines the function of cardiac microvascular endothelial cells. These findings suggest the potential of targeting the WDPCP/MAPK axis as an intervention strategy for neonatal CHDs.https://doi.org/10.1002/pul2.70013congenital heart defects (CHDs)EMCNleucineMAPK/ERKWDPCP |
| spellingShingle | Wei Hong Guozhou You Zhongming Luo Mingxiang Zhang Jian Chen High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects Pulmonary Circulation congenital heart defects (CHDs) EMCN leucine MAPK/ERK WDPCP |
| title | High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects |
| title_full | High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects |
| title_fullStr | High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects |
| title_full_unstemmed | High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects |
| title_short | High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects |
| title_sort | high gestational leucine level dampens wdpcp mapk signaling to impair the emt and migration of cardiac microvascular endothelial cells in congenital heart defects |
| topic | congenital heart defects (CHDs) EMCN leucine MAPK/ERK WDPCP |
| url | https://doi.org/10.1002/pul2.70013 |
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