Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Baccam, Gabriel C., Xie, Jian, Jin, Xin, Park, Hyejung, Wang, Bing, Husson, Hervé, Ibraghimov-Beskrovnaya, Oxana, Huang, Chou-Long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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
_version_ 1784720782286389248
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
work_keys_str_mv AT baccamgabrielc glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT xiejian glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT jinxin glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT parkhyejung glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT wangbing glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT hussonherve glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT ibraghimovbeskrovnayaoxana glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease
AT huangchoulong glucosylceramidesynthaseinhibitionprotectsagainstcardiachypertrophyinchronickidneydisease