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Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family
BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease. We previously demonstrated that disruption of calcium-activated potassium (K(Ca)) channel activity is involved in homocysteine-induced dilatory dysfunction of porcine coronary arteries. Recently we repo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106027/ https://www.ncbi.nlm.nih.gov/pubmed/33987323 http://dx.doi.org/10.21037/atm-20-6821 |
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author | Sun, Wen-Tao Xue, Hong-Mei Hou, Hai-Tao Chen, Huan-Xin Wang, Jun He, Guo-Wei Yang, Qin |
author_facet | Sun, Wen-Tao Xue, Hong-Mei Hou, Hai-Tao Chen, Huan-Xin Wang, Jun He, Guo-Wei Yang, Qin |
author_sort | Sun, Wen-Tao |
collection | PubMed |
description | BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease. We previously demonstrated that disruption of calcium-activated potassium (K(Ca)) channel activity is involved in homocysteine-induced dilatory dysfunction of porcine coronary arteries. Recently we reported that the K(Ca) channel family, including large-, intermediate-, and small-conductance K(Ca) (BK(Ca), IK(Ca), and SK(Ca)) subtypes, are abundantly expressed in human internal mammary artery (IMA). In this study, we further investigated whether homocysteine affects the expression and functionality of the K(Ca) channel family in this commonly used graft for coronary artery bypass surgery (CABG). METHODS: Residual IMA segments obtained from patients undergoing CABG were studied in a myograph for the role of K(Ca) subtypes in both vasorelaxation and vasoconstriction. The expression and distribution of K(Ca) subtypes were detected by Western blot and immunohistochemistry. RESULTS: Both the BK(Ca) channel activator NS1619 and the IK(Ca)/SK(Ca) channel activator NS309 evoked significant IMA relaxation. Homocysteine exposure suppressed NS1619-induced relaxation whereas showed no influence on NS309-induced response. Blockade of BK(Ca) but not IK(Ca) and SK(Ca) subtypes significantly suppressed acetylcholine-induced relaxation and enhanced U46619-induced contraction. Homocysteine compromised the vasodilating activity of the BK(Ca) subtype in IMA, associated with a lowered protein level of the BK(Ca) β1-subunit. Homocysteine potentiated the role of IK(Ca) and SK(Ca) subtypes in mediating endothelium-dependent relaxation without affecting the expression of these channels. CONCLUSIONS: Homocysteine reduces the expression of BK(Ca) β1-subunit and compromises the vasodilating activity of BK(Ca) channels in IMA. Unlike BK(Ca), IK(Ca) and SK(Ca) subtypes are unessential for IMA vasoregulation, whereas the loss of BK(Ca) functionality in hyperhomocysteinemia enhances the role of IK(Ca) and SK(Ca) subtypes in mediating endothelial dilator function. Targeting BK(Ca) channels may form a strategy to improve the postoperative graft performance in CABG patients with hyperhomocysteinemia who receive IMA grafting. |
format | Online Article Text |
id | pubmed-8106027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-81060272021-05-12 Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family Sun, Wen-Tao Xue, Hong-Mei Hou, Hai-Tao Chen, Huan-Xin Wang, Jun He, Guo-Wei Yang, Qin Ann Transl Med Original Article BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease. We previously demonstrated that disruption of calcium-activated potassium (K(Ca)) channel activity is involved in homocysteine-induced dilatory dysfunction of porcine coronary arteries. Recently we reported that the K(Ca) channel family, including large-, intermediate-, and small-conductance K(Ca) (BK(Ca), IK(Ca), and SK(Ca)) subtypes, are abundantly expressed in human internal mammary artery (IMA). In this study, we further investigated whether homocysteine affects the expression and functionality of the K(Ca) channel family in this commonly used graft for coronary artery bypass surgery (CABG). METHODS: Residual IMA segments obtained from patients undergoing CABG were studied in a myograph for the role of K(Ca) subtypes in both vasorelaxation and vasoconstriction. The expression and distribution of K(Ca) subtypes were detected by Western blot and immunohistochemistry. RESULTS: Both the BK(Ca) channel activator NS1619 and the IK(Ca)/SK(Ca) channel activator NS309 evoked significant IMA relaxation. Homocysteine exposure suppressed NS1619-induced relaxation whereas showed no influence on NS309-induced response. Blockade of BK(Ca) but not IK(Ca) and SK(Ca) subtypes significantly suppressed acetylcholine-induced relaxation and enhanced U46619-induced contraction. Homocysteine compromised the vasodilating activity of the BK(Ca) subtype in IMA, associated with a lowered protein level of the BK(Ca) β1-subunit. Homocysteine potentiated the role of IK(Ca) and SK(Ca) subtypes in mediating endothelium-dependent relaxation without affecting the expression of these channels. CONCLUSIONS: Homocysteine reduces the expression of BK(Ca) β1-subunit and compromises the vasodilating activity of BK(Ca) channels in IMA. Unlike BK(Ca), IK(Ca) and SK(Ca) subtypes are unessential for IMA vasoregulation, whereas the loss of BK(Ca) functionality in hyperhomocysteinemia enhances the role of IK(Ca) and SK(Ca) subtypes in mediating endothelial dilator function. Targeting BK(Ca) channels may form a strategy to improve the postoperative graft performance in CABG patients with hyperhomocysteinemia who receive IMA grafting. AME Publishing Company 2021-04 /pmc/articles/PMC8106027/ /pubmed/33987323 http://dx.doi.org/10.21037/atm-20-6821 Text en 2021 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Sun, Wen-Tao Xue, Hong-Mei Hou, Hai-Tao Chen, Huan-Xin Wang, Jun He, Guo-Wei Yang, Qin Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title | Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title_full | Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title_fullStr | Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title_full_unstemmed | Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title_short | Homocysteine alters vasoreactivity of human internal mammary artery by affecting the K(Ca) channel family |
title_sort | homocysteine alters vasoreactivity of human internal mammary artery by affecting the k(ca) channel family |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106027/ https://www.ncbi.nlm.nih.gov/pubmed/33987323 http://dx.doi.org/10.21037/atm-20-6821 |
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