High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension
Abstract Background The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. Methods This study...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06483-6 |
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| author | Baoling Bai Lingyun Liu Yanyan Liu Shuangshuang Yang Haojie Wu Kexin Zhang Lin Shi Qin Zhang |
| author_facet | Baoling Bai Lingyun Liu Yanyan Liu Shuangshuang Yang Haojie Wu Kexin Zhang Lin Shi Qin Zhang |
| author_sort | Baoling Bai |
| collection | DOAJ |
| description | Abstract Background The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. Methods This study utilized plasma samples from 27 control children and 27 children with HHYP (aged 8 ~ 16 years) for TMT6-labeled proteomic quantification, identifying significant altered proteins. Bioinformatics analysis revealed pathway alterations. Verification was carried out via parallel reaction monitoring (PRM) and western blot (WB) analyses. Additionally, a rat model of HHYP induced by high methionine diets, and umbilical vein endothelial cell models exposed to high homocysteine (hcy) levels were developed to investigate the molecular underpinnings further. Protein expression changes and epigenetic modifications were assessed using WB, immunohistochemistry (IHC), and ChIP-qPCR techniques. Results Key findings indicated that 357 proteins and 69 pathways were altered in children with HHYP. Specifically, 12 proteins within the fluid shear stress and atherosclerosis (FSSA) pathway showed differential expression, including the downregulation of TRX1 and GPX1 and the upregulation of ICAM1. The same expression patterns were noted in both the HHYP rat aortic tissues and the high hcy cultured endothelial cells. Moreover, elevated H3K79hcy modification levels were observed alongside epigenetic regulation of genes related to the FSSA pathway. Importantly, folic acid (FA), a medication frequently used in the clinical treatment of HHYP, has been demonstrated to effectively reverse H3K79hcy modifications and restore the disrupted FSSA pathway in both animal models and cell cultures. Conclusions The present study suggests that HHcy may contribute to hypertension through the epigenetic dysregulation of the FSSA pathway mediated by H3K79hcy. Furthermore, the pediatric proteomics data gleaned from this study offer new clinical insights into the pathophysiology of HHYP in children. |
| format | Article |
| id | doaj-art-8018bbf562154fd88f13f541c2438c83 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-8018bbf562154fd88f13f541c2438c832025-08-20T03:53:12ZengBMCJournal of Translational Medicine1479-58762025-05-0123111710.1186/s12967-025-06483-6High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertensionBaoling Bai0Lingyun Liu1Yanyan Liu2Shuangshuang Yang3Haojie Wu4Kexin Zhang5Lin Shi6Qin Zhang7Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsDepartment of Cardiology, Capital Center for Children’s Health, Capital Medical UniversityBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsDepartment of Cardiology, Capital Center for Children’s Health, Capital Medical UniversityBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsDepartment of Cardiology, Capital Center for Children’s Health, Capital Medical UniversityBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsAbstract Background The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. Methods This study utilized plasma samples from 27 control children and 27 children with HHYP (aged 8 ~ 16 years) for TMT6-labeled proteomic quantification, identifying significant altered proteins. Bioinformatics analysis revealed pathway alterations. Verification was carried out via parallel reaction monitoring (PRM) and western blot (WB) analyses. Additionally, a rat model of HHYP induced by high methionine diets, and umbilical vein endothelial cell models exposed to high homocysteine (hcy) levels were developed to investigate the molecular underpinnings further. Protein expression changes and epigenetic modifications were assessed using WB, immunohistochemistry (IHC), and ChIP-qPCR techniques. Results Key findings indicated that 357 proteins and 69 pathways were altered in children with HHYP. Specifically, 12 proteins within the fluid shear stress and atherosclerosis (FSSA) pathway showed differential expression, including the downregulation of TRX1 and GPX1 and the upregulation of ICAM1. The same expression patterns were noted in both the HHYP rat aortic tissues and the high hcy cultured endothelial cells. Moreover, elevated H3K79hcy modification levels were observed alongside epigenetic regulation of genes related to the FSSA pathway. Importantly, folic acid (FA), a medication frequently used in the clinical treatment of HHYP, has been demonstrated to effectively reverse H3K79hcy modifications and restore the disrupted FSSA pathway in both animal models and cell cultures. Conclusions The present study suggests that HHcy may contribute to hypertension through the epigenetic dysregulation of the FSSA pathway mediated by H3K79hcy. Furthermore, the pediatric proteomics data gleaned from this study offer new clinical insights into the pathophysiology of HHYP in children.https://doi.org/10.1186/s12967-025-06483-6Hyperhomocysteinemia (HHcy)HHcy-type hypertension (HHYP)TMT-6plex labelingFluid shear stress and atherosclerosis (FSSA)H3K79hcy |
| spellingShingle | Baoling Bai Lingyun Liu Yanyan Liu Shuangshuang Yang Haojie Wu Kexin Zhang Lin Shi Qin Zhang High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension Journal of Translational Medicine Hyperhomocysteinemia (HHcy) HHcy-type hypertension (HHYP) TMT-6plex labeling Fluid shear stress and atherosclerosis (FSSA) H3K79hcy |
| title | High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension |
| title_full | High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension |
| title_fullStr | High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension |
| title_full_unstemmed | High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension |
| title_short | High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension |
| title_sort | high hcy regulates fluid shear stress pathway activity through histone h3k79 homocysteinylation in hyperhomocysteinemia related child hypertension |
| topic | Hyperhomocysteinemia (HHcy) HHcy-type hypertension (HHYP) TMT-6plex labeling Fluid shear stress and atherosclerosis (FSSA) H3K79hcy |
| url | https://doi.org/10.1186/s12967-025-06483-6 |
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