Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation
Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (<i>Scd1</i>), in different experimental models of heart failure induced by advanced atherosclerosis, c...
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| Format: | Article |
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MDPI AG
2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/18/9883 |
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| author | Joshua Abd Alla Yahya F. Jamous Ursula Quitterer |
| author_facet | Joshua Abd Alla Yahya F. Jamous Ursula Quitterer |
| author_sort | Joshua Abd Alla |
| collection | DOAJ |
| description | Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (<i>Scd1</i>), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of <i>Scd1</i>/<i>SCD</i> in heart failure is not clear, we investigated the impact of cardiac <i>SCD</i> upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of <i>SCD</i>. Echocardiographic examination showed that 4.9-fold-increased <i>SCD</i> levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-<i>SCD</i> mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-<i>SCD</i> mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-<i>SCD</i> hearts was significantly up-regulated. In transfected HEK cells, the expression of <i>SCD</i> increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that <i>SCD</i> promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein. |
| first_indexed | 2024-03-10T07:35:34Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:35:34Z |
| publishDate | 2021-09-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-37f6f411594d4e06a725039f196213ba2023-11-22T13:29:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-012218988310.3390/ijms22189883Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-RegulationJoshua Abd Alla0Yahya F. Jamous1Ursula Quitterer2Molecular Pharmacology, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, SwitzerlandMolecular Pharmacology, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, SwitzerlandMolecular Pharmacology, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, SwitzerlandHeart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (<i>Scd1</i>), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of <i>Scd1</i>/<i>SCD</i> in heart failure is not clear, we investigated the impact of cardiac <i>SCD</i> upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of <i>SCD</i>. Echocardiographic examination showed that 4.9-fold-increased <i>SCD</i> levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-<i>SCD</i> mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-<i>SCD</i> mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-<i>SCD</i> hearts was significantly up-regulated. In transfected HEK cells, the expression of <i>SCD</i> increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that <i>SCD</i> promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein.https://www.mdpi.com/1422-0067/22/18/9883SCDScd1transgenic miceheart failurelipid overloadangiotensin II |
| spellingShingle | Joshua Abd Alla Yahya F. Jamous Ursula Quitterer Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation International Journal of Molecular Sciences SCD Scd1 transgenic mice heart failure lipid overload angiotensin II |
| title | Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation |
| title_full | Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation |
| title_fullStr | Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation |
| title_full_unstemmed | Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation |
| title_short | Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation |
| title_sort | stearoyl coa desaturase scd induces cardiac dysfunction with cardiac lipid overload and angiotensin ii at1 receptor protein up regulation |
| topic | SCD Scd1 transgenic mice heart failure lipid overload angiotensin II |
| url | https://www.mdpi.com/1422-0067/22/18/9883 |
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