Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity
Abstract Background Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transpor...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12933-019-0889-y |
| _version_ | 1818996137249472512 |
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| author | Akira Yoshii Tomohisa Nagoshi Yusuke Kashiwagi Haruka Kimura Yoshiro Tanaka Yuhei Oi Keiichi Ito Takuya Yoshino Toshikazu D. Tanaka Michihiro Yoshimura |
| author_facet | Akira Yoshii Tomohisa Nagoshi Yusuke Kashiwagi Haruka Kimura Yoshiro Tanaka Yuhei Oi Keiichi Ito Takuya Yoshino Toshikazu D. Tanaka Michihiro Yoshimura |
| author_sort | Akira Yoshii |
| collection | DOAJ |
| description | Abstract Background Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia–reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia–reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised. |
| first_indexed | 2024-12-20T21:24:57Z |
| format | Article |
| id | doaj.art-3220f73d7800453f8dd8a39baafb1db3 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-20T21:24:57Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-3220f73d7800453f8dd8a39baafb1db32022-12-21T19:26:10ZengBMCCardiovascular Diabetology1475-28402019-07-0118111410.1186/s12933-019-0889-yCardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesityAkira Yoshii0Tomohisa Nagoshi1Yusuke Kashiwagi2Haruka Kimura3Yoshiro Tanaka4Yuhei Oi5Keiichi Ito6Takuya Yoshino7Toshikazu D. Tanaka8Michihiro Yoshimura9Division of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineDivision of Cardiology, Department of Internal Medicine, The Jikei University School of MedicineAbstract Background Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia–reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia–reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.http://link.springer.com/article/10.1186/s12933-019-0889-ySGLT1PhlorizinSGLT2-inhibitorGLUT4Insulin resistanceIschemia–reperfusion injury |
| spellingShingle | Akira Yoshii Tomohisa Nagoshi Yusuke Kashiwagi Haruka Kimura Yoshiro Tanaka Yuhei Oi Keiichi Ito Takuya Yoshino Toshikazu D. Tanaka Michihiro Yoshimura Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity Cardiovascular Diabetology SGLT1 Phlorizin SGLT2-inhibitor GLUT4 Insulin resistance Ischemia–reperfusion injury |
| title | Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity |
| title_full | Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity |
| title_fullStr | Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity |
| title_full_unstemmed | Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity |
| title_short | Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity |
| title_sort | cardiac ischemia reperfusion injury under insulin resistant conditions sglt1 but not sglt2 plays a compensatory protective role in diet induced obesity |
| topic | SGLT1 Phlorizin SGLT2-inhibitor GLUT4 Insulin resistance Ischemia–reperfusion injury |
| url | http://link.springer.com/article/10.1186/s12933-019-0889-y |
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