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Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction
The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increase...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554365/ https://www.ncbi.nlm.nih.gov/pubmed/23069627 http://dx.doi.org/10.2337/db12-0350 |
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author | Hua, Yinan Zhang, Yingmei Dolence, Julia Shi, Guo-Ping Ren, Jun Nair, Sreejayan |
author_facet | Hua, Yinan Zhang, Yingmei Dolence, Julia Shi, Guo-Ping Ren, Jun Nair, Sreejayan |
author_sort | Hua, Yinan |
collection | PubMed |
description | The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening. All these changes were reconciled in cathepsin K knockout mice. Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet–fed mice. High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout. Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm. In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid–induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules. Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies. |
format | Online Article Text |
id | pubmed-3554365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-35543652014-02-01 Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction Hua, Yinan Zhang, Yingmei Dolence, Julia Shi, Guo-Ping Ren, Jun Nair, Sreejayan Diabetes Obesity Studies The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening. All these changes were reconciled in cathepsin K knockout mice. Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet–fed mice. High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout. Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm. In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid–induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules. Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies. American Diabetes Association 2013-02 2013-01-17 /pmc/articles/PMC3554365/ /pubmed/23069627 http://dx.doi.org/10.2337/db12-0350 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Obesity Studies Hua, Yinan Zhang, Yingmei Dolence, Julia Shi, Guo-Ping Ren, Jun Nair, Sreejayan Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title | Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title_full | Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title_fullStr | Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title_full_unstemmed | Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title_short | Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction |
title_sort | cathepsin k knockout mitigates high-fat diet–induced cardiac hypertrophy and contractile dysfunction |
topic | Obesity Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554365/ https://www.ncbi.nlm.nih.gov/pubmed/23069627 http://dx.doi.org/10.2337/db12-0350 |
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