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Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease
A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167280/ https://www.ncbi.nlm.nih.gov/pubmed/35660779 http://dx.doi.org/10.1038/s41598-022-13390-z |
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author | Baccam, Gabriel C. Xie, Jian Jin, Xin Park, Hyejung Wang, Bing Husson, Hervé Ibraghimov-Beskrovnaya, Oxana Huang, Chou-Long |
author_facet | Baccam, Gabriel C. Xie, Jian Jin, Xin Park, Hyejung Wang, Bing Husson, Hervé Ibraghimov-Beskrovnaya, Oxana Huang, Chou-Long |
author_sort | Baccam, Gabriel C. |
collection | PubMed |
description | A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides. |
format | Online Article Text |
id | pubmed-9167280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91672802022-06-06 Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease Baccam, Gabriel C. Xie, Jian Jin, Xin Park, Hyejung Wang, Bing Husson, Hervé Ibraghimov-Beskrovnaya, Oxana Huang, Chou-Long Sci Rep Article A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides. Nature Publishing Group UK 2022-06-04 /pmc/articles/PMC9167280/ /pubmed/35660779 http://dx.doi.org/10.1038/s41598-022-13390-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Baccam, Gabriel C. Xie, Jian Jin, Xin Park, Hyejung Wang, Bing Husson, Hervé Ibraghimov-Beskrovnaya, Oxana Huang, Chou-Long Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title | Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title_full | Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title_fullStr | Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title_full_unstemmed | Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title_short | Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
title_sort | glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167280/ https://www.ncbi.nlm.nih.gov/pubmed/35660779 http://dx.doi.org/10.1038/s41598-022-13390-z |
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