SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy
Background: Elevated myocardial intracellular sodium ([Na+]i) was shown to decrease mitochondrial calcium ([Ca2+]MITO) via mitochondrial sodium/calcium exchanger (NCXMITO), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU)...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223000987 |
| _version_ | 1797894765877919744 |
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| author | Dominique Croteau Tomas Baka Sara Young Huamei He Jordan M. Chambers Fuzhong Qin Marcello Panagia David R. Pimentel James A. Balschi Wilson S. Colucci Ivan Luptak |
| author_facet | Dominique Croteau Tomas Baka Sara Young Huamei He Jordan M. Chambers Fuzhong Qin Marcello Panagia David R. Pimentel James A. Balschi Wilson S. Colucci Ivan Luptak |
| author_sort | Dominique Croteau |
| collection | DOAJ |
| description | Background: Elevated myocardial intracellular sodium ([Na+]i) was shown to decrease mitochondrial calcium ([Ca2+]MITO) via mitochondrial sodium/calcium exchanger (NCXMITO), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU) improved energetic deficit and contractile dysfunction in a mouse model of high fat, high sucrose (HFHS) diet-induced diabetic cardiomyopathy (DCMP). As SGLT2is were shown to lower [Na+]i in isolated cardiomyocytes, we hypothesized that energetic improvement in DCMP is at least partially mediated by a decrease in abnormally elevated myocardial [Na+]i. Methods: Forty-two eight-week-old male C57BL/6J mice were fed a control or HFHS diet for six months. In the last month, a subgroup of HFHS-fed mice was treated with ERTU. At the end of the study, left ventricular contractile function and energetics were measured simultaneously in isolated beating hearts by 31P NMR (Nuclear Magnetic Resonance) spectroscopy. A subset of untreated HFHS hearts was perfused with vehicle vs. CGP 37157, an NCXMITO inhibitor. Myocardial [Na+]i was measured by 23Na NMR spectroscopy. Results: HFHS hearts showed diastolic dysfunction, decreased contractile reserve, and impaired energetics as reflected by decreased phosphocreatine (PCr) and PCr/ATP ratio. Myocardial [Na+]i was elevated > 2-fold in HFHS (vs. control diet). ERTU reversed the impairments in HFHS hearts to levels similar to or better than control diet and decreased myocardial [Na+]i to control levels. CGP 37157 normalized the PCr/ATP ratio in HFHS hearts. Conclusions: Elevated myocardial [Na+]i contributes to mitochondrial and contractile dysfunction in DCMP. Targeting myocardial [Na+]i and/or NCXMITO may be an effective strategy in DCMP and other forms of heart disease associated with elevated myocardial [Na+]i. |
| first_indexed | 2024-04-10T07:14:32Z |
| format | Article |
| id | doaj.art-ddbf2c50d47847a383f78995232ae6e7 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-10T07:14:32Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-ddbf2c50d47847a383f78995232ae6e72023-02-26T04:26:22ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-04-01160114310SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathyDominique Croteau0Tomas Baka1Sara Young2Huamei He3Jordan M. Chambers4Fuzhong Qin5Marcello Panagia6David R. Pimentel7James A. Balschi8Wilson S. Colucci9Ivan Luptak10Myocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAPhysiological NMR Core Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAPhysiological NMR Core Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USAMyocardial Biology Unit, Boston University School of Medicine, Boston, MA, USA; Correspondence to: Cardiovascular Medicine Section, Boston University Medical Center, 650 Albany St, Room 704B, Boston, MA 02118, USA.Background: Elevated myocardial intracellular sodium ([Na+]i) was shown to decrease mitochondrial calcium ([Ca2+]MITO) via mitochondrial sodium/calcium exchanger (NCXMITO), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU) improved energetic deficit and contractile dysfunction in a mouse model of high fat, high sucrose (HFHS) diet-induced diabetic cardiomyopathy (DCMP). As SGLT2is were shown to lower [Na+]i in isolated cardiomyocytes, we hypothesized that energetic improvement in DCMP is at least partially mediated by a decrease in abnormally elevated myocardial [Na+]i. Methods: Forty-two eight-week-old male C57BL/6J mice were fed a control or HFHS diet for six months. In the last month, a subgroup of HFHS-fed mice was treated with ERTU. At the end of the study, left ventricular contractile function and energetics were measured simultaneously in isolated beating hearts by 31P NMR (Nuclear Magnetic Resonance) spectroscopy. A subset of untreated HFHS hearts was perfused with vehicle vs. CGP 37157, an NCXMITO inhibitor. Myocardial [Na+]i was measured by 23Na NMR spectroscopy. Results: HFHS hearts showed diastolic dysfunction, decreased contractile reserve, and impaired energetics as reflected by decreased phosphocreatine (PCr) and PCr/ATP ratio. Myocardial [Na+]i was elevated > 2-fold in HFHS (vs. control diet). ERTU reversed the impairments in HFHS hearts to levels similar to or better than control diet and decreased myocardial [Na+]i to control levels. CGP 37157 normalized the PCr/ATP ratio in HFHS hearts. Conclusions: Elevated myocardial [Na+]i contributes to mitochondrial and contractile dysfunction in DCMP. Targeting myocardial [Na+]i and/or NCXMITO may be an effective strategy in DCMP and other forms of heart disease associated with elevated myocardial [Na+]i.http://www.sciencedirect.com/science/article/pii/S0753332223000987Cardiac energeticsContractile functionDiabetic cardiomyopathyErtugliflozinMyocardial intracellular sodiumSodium-glucose co-transporter 2 (SGLT2) inhibitor |
| spellingShingle | Dominique Croteau Tomas Baka Sara Young Huamei He Jordan M. Chambers Fuzhong Qin Marcello Panagia David R. Pimentel James A. Balschi Wilson S. Colucci Ivan Luptak SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy Biomedicine & Pharmacotherapy Cardiac energetics Contractile function Diabetic cardiomyopathy Ertugliflozin Myocardial intracellular sodium Sodium-glucose co-transporter 2 (SGLT2) inhibitor |
| title | SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy |
| title_full | SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy |
| title_fullStr | SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy |
| title_full_unstemmed | SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy |
| title_short | SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy |
| title_sort | sglt2 inhibitor ertugliflozin decreases elevated intracellular sodium and improves energetics and contractile function in diabetic cardiomyopathy |
| topic | Cardiac energetics Contractile function Diabetic cardiomyopathy Ertugliflozin Myocardial intracellular sodium Sodium-glucose co-transporter 2 (SGLT2) inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223000987 |
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