No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation
Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-07-01
|
| Series: | Nutrients |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6643/12/8/2182 |
| _version_ | 1797561620267794432 |
|---|---|
| author | Courtney A. Whalen Floyd J. Mattie Cristina Florindo Bertrand van Zelst Neil K. Huang Isabel Tavares de Almeida Sandra G. Heil Thomas Neuberger A. Catharine Ross Rita Castro |
| author_facet | Courtney A. Whalen Floyd J. Mattie Cristina Florindo Bertrand van Zelst Neil K. Huang Isabel Tavares de Almeida Sandra G. Heil Thomas Neuberger A. Catharine Ross Rita Castro |
| author_sort | Courtney A. Whalen |
| collection | DOAJ |
| description | Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (<i>ApoE</i> <sup>−/−</sup>) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation. |
| first_indexed | 2024-03-10T18:17:30Z |
| format | Article |
| id | doaj.art-fcbb753367c445cba672e60599aca5d8 |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-10T18:17:30Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-fcbb753367c445cba672e60599aca5d82023-11-20T07:38:40ZengMDPI AGNutrients2072-66432020-07-01128218210.3390/nu12082182No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone MethylationCourtney A. Whalen0Floyd J. Mattie1Cristina Florindo2Bertrand van Zelst3Neil K. Huang4Isabel Tavares de Almeida5Sandra G. Heil6Thomas Neuberger7A. Catharine Ross8Rita Castro9Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USAFaculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalDepartment of Clinical Chemistry, Medical Center Rotterdam, Erasmus MC University, 3015 GD Rotterdam, The NetherlandsDepartment of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USAFaculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalDepartment of Clinical Chemistry, Medical Center Rotterdam, Erasmus MC University, 3015 GD Rotterdam, The NetherlandsHuck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USAHyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (<i>ApoE</i> <sup>−/−</sup>) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation.https://www.mdpi.com/2072-6643/12/8/2182homocysteine and vascular diseaseH3K27me3epigeneticsatherosclerosisMRI (magnetic resonance imaging) |
| spellingShingle | Courtney A. Whalen Floyd J. Mattie Cristina Florindo Bertrand van Zelst Neil K. Huang Isabel Tavares de Almeida Sandra G. Heil Thomas Neuberger A. Catharine Ross Rita Castro No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation Nutrients homocysteine and vascular disease H3K27me3 epigenetics atherosclerosis MRI (magnetic resonance imaging) |
| title | No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation |
| title_full | No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation |
| title_fullStr | No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation |
| title_full_unstemmed | No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation |
| title_short | No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation |
| title_sort | no effect of diet induced mild hyperhomocysteinemia on vascular methylating capacity atherosclerosis progression and specific histone methylation |
| topic | homocysteine and vascular disease H3K27me3 epigenetics atherosclerosis MRI (magnetic resonance imaging) |
| url | https://www.mdpi.com/2072-6643/12/8/2182 |
| work_keys_str_mv | AT courtneyawhalen noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT floydjmattie noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT cristinaflorindo noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT bertrandvanzelst noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT neilkhuang noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT isabeltavaresdealmeida noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT sandragheil noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT thomasneuberger noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT acatharineross noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation AT ritacastro noeffectofdietinducedmildhyperhomocysteinemiaonvascularmethylatingcapacityatherosclerosisprogressionandspecifichistonemethylation |