Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy
Abstract Background Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipi...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-023-02057-2 |
| _version_ | 1797578323944013824 |
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| author | Sarah Costantino Alessandro Mengozzi Srividya Velagapudi Shafeeq Ahmed Mohammed Era Gorica Alexander Akhmedov Alessia Mongelli Nicola Riccardo Pugliese Stefano Masi Agostino Virdis Andreas Hülsmeier Christian Matthias Matter Thorsten Hornemann Giovanni Melina Frank Ruschitzka Thomas Felix Luscher Francesco Paneni |
| author_facet | Sarah Costantino Alessandro Mengozzi Srividya Velagapudi Shafeeq Ahmed Mohammed Era Gorica Alexander Akhmedov Alessia Mongelli Nicola Riccardo Pugliese Stefano Masi Agostino Virdis Andreas Hülsmeier Christian Matthias Matter Thorsten Hornemann Giovanni Melina Frank Ruschitzka Thomas Felix Luscher Francesco Paneni |
| author_sort | Sarah Costantino |
| collection | DOAJ |
| description | Abstract Background Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. Methods db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. Results rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. Conclusions In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development. Graphical Abstract |
| first_indexed | 2024-03-10T22:20:18Z |
| format | Article |
| id | doaj.art-54a8ca9133bf4bca90b873b095b4112e |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-03-10T22:20:18Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-54a8ca9133bf4bca90b873b095b4112e2023-11-19T12:17:34ZengBMCCardiovascular Diabetology1475-28402023-11-0122111310.1186/s12933-023-02057-2Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathySarah Costantino0Alessandro Mengozzi1Srividya Velagapudi2Shafeeq Ahmed Mohammed3Era Gorica4Alexander Akhmedov5Alessia Mongelli6Nicola Riccardo Pugliese7Stefano Masi8Agostino Virdis9Andreas Hülsmeier10Christian Matthias Matter11Thorsten Hornemann12Giovanni Melina13Frank Ruschitzka14Thomas Felix Luscher15Francesco Paneni16Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichCenter for Molecular Cardiology, University of ZurichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichCenter for Molecular Cardiology, University of ZurichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichDepartment of Clinical and Experimental Medicine, University of PisaDepartment of Clinical and Experimental Medicine, University of PisaDepartment of Clinical and Experimental Medicine, University of PisaInstitute for Clinical Chemistry, University Hospital and University of ZürichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichInstitute for Clinical Chemistry, University Hospital and University of ZürichDepartment of Clinical and Molecular Medicine, Sapienza University of RomeCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichCenter for Molecular Cardiology, University of ZurichCenter for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of ZurichAbstract Background Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. Methods db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. Results rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. Conclusions In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development. Graphical Abstracthttps://doi.org/10.1186/s12933-023-02057-2Metabolic cardiomyopathySirt1LipidomeDiabetesCardiometabolicTherapy |
| spellingShingle | Sarah Costantino Alessandro Mengozzi Srividya Velagapudi Shafeeq Ahmed Mohammed Era Gorica Alexander Akhmedov Alessia Mongelli Nicola Riccardo Pugliese Stefano Masi Agostino Virdis Andreas Hülsmeier Christian Matthias Matter Thorsten Hornemann Giovanni Melina Frank Ruschitzka Thomas Felix Luscher Francesco Paneni Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy Cardiovascular Diabetology Metabolic cardiomyopathy Sirt1 Lipidome Diabetes Cardiometabolic Therapy |
| title | Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy |
| title_full | Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy |
| title_fullStr | Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy |
| title_full_unstemmed | Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy |
| title_short | Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy |
| title_sort | treatment with recombinant sirt1 rewires the cardiac lipidome and rescues diabetes related metabolic cardiomyopathy |
| topic | Metabolic cardiomyopathy Sirt1 Lipidome Diabetes Cardiometabolic Therapy |
| url | https://doi.org/10.1186/s12933-023-02057-2 |
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