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Goedeke L, Ma Y, Gaspar RC, Nasiri A, Lee J, Zhang D, Galsgaard KD, Hu X, Zhang J, Guerrera N, Li X, LaMoia T, Hubbard BT, Haedersdal S, Wu X, Stack J, Dufour S, Butrico GM, Kahn M, Perry RJ, Cline GW, Young LH, Shulman GI. SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts. J Clin Invest 2024; 134:e176708. [PMID: 39680452 PMCID: PMC11645152 DOI: 10.1172/jci176708] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 10/17/2024] [Indexed: 12/18/2024] Open
Abstract
Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
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Affiliation(s)
- Leigh Goedeke
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Medicine (Cardiology) and The Cardiovascular Research Institute and
- Department of Medicine (Endocrinology) and The Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yina Ma
- Department of Internal Medicine (Cardiovascular Medicine) and The Yale Cardiovascular Research Center, Yale School of Medicine, New Haven Connecticut, USA
| | - Rafael C. Gaspar
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Ali Nasiri
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Jieun Lee
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Dongyan Zhang
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Katrine Douglas Galsgaard
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Xiaoyue Hu
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Jiasheng Zhang
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Nicole Guerrera
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Xiruo Li
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
| | - Traci LaMoia
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
| | - Brandon T. Hubbard
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
| | - Sofie Haedersdal
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Clinical Research, Copenhagen University Hospital, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Xiaohong Wu
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - John Stack
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Sylvie Dufour
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Gina Marie Butrico
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Mario Kahn
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Rachel J. Perry
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
| | - Gary W. Cline
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
| | - Lawrence H. Young
- Department of Internal Medicine (Cardiovascular Medicine) and The Yale Cardiovascular Research Center, Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
| | - Gerald I. Shulman
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven Connecticut, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
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Chen YR, Zhu FY, Zhou R. SGLT2 inhibitors for alleviating heart failure through non-hypoglycemic mechanisms. Front Cardiovasc Med 2024; 11:1494882. [PMID: 39717441 PMCID: PMC11663900 DOI: 10.3389/fcvm.2024.1494882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/12/2024] [Indexed: 12/25/2024] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors afford significant cardiovascular benefits to patients with diabetes mellitus and heart failure. Three large randomized clinical trials (EMPAREG-Outcomes, DECLARE-TIMI58, and DAPA-HF) have shown that SGLT2 inhibitors prevent cardiovascular events and reduce the risk of death and hospital admission resulting from heart failure. Patients without type 2 diabetes mellitus (T2DM) also experience a similar degree of cardiovascular benefit as those with T2DM do. SGLT2 inhibitors could improve cardiac function through potential non-hypoglycemic mechanisms, including the reduction of the circulatory volume load, regulation of energy metabolism, maintenance of ion homeostasis, alleviation of inflammation and oxidative stress, and direct inhibition of cardiac SGLT1 receptors and antimyocardial fibrosis. This article reviews the mechanism through which SGLT2 inhibitors prevent/alleviate heart failure through non-hypoglycemic pathways, to support their use for the treatment of heart failure in non-T2DM patients.
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Affiliation(s)
| | | | - Rong Zhou
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Shi Y, Zhao L, Wang J, Liu X, Bai Y, Cong H, Li X. Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis. Cardiovasc Diabetol 2024; 23:269. [PMID: 39044275 PMCID: PMC11267814 DOI: 10.1186/s12933-024-02366-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/16/2024] [Indexed: 07/25/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.
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Affiliation(s)
- Ying Shi
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Lili Zhao
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Jing Wang
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Xiankun Liu
- Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Yiming Bai
- Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Hongliang Cong
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China.
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China.
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China.
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China.
| | - Ximing Li
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China.
- Chest Hospital, Tianjin University, Tianjin, 300072, China.
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China.
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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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Rabbani N, Thornalley PJ. Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications. Front Endocrinol (Lausanne) 2024; 14:1268308. [PMID: 38292764 PMCID: PMC10824962 DOI: 10.3389/fendo.2023.1268308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/12/2023] [Indexed: 02/01/2024] Open
Abstract
Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.
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Affiliation(s)
| | - Paul J. Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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Vaziri Z, Saleki K, Aram C, Alijanizadeh P, Pourahmad R, Azadmehr A, Ziaei N. Empagliflozin treatment of cardiotoxicity: A comprehensive review of clinical, immunobiological, neuroimmune, and therapeutic implications. Biomed Pharmacother 2023; 168:115686. [PMID: 37839109 DOI: 10.1016/j.biopha.2023.115686] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 10/03/2023] [Accepted: 10/08/2023] [Indexed: 10/17/2023] Open
Abstract
Cancer and cardiovascular disorders are known as the two main leading causes of mortality worldwide. Cardiotoxicity is a critical and common adverse effect of cancer-related chemotherapy. Chemotherapy-induced cardiotoxicity has been associated with various cancer treatments, such as anthracyclines, immune checkpoint inhibitors, and kinase inhibitors. Different methods have been reported for the management of chemotherapy-induced cardiotoxicity. In this regard, sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of antidiabetic agents, have recently been applied to manage heart failure patients. Further, SGLT2i drugs such as EMPA exert protective cardiac and systemic effects. Moreover, it can reduce inflammation through the mediation of major inflammatory components, such as Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasomes, Adenosine 5'-monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal kinase (JNK) pathways, Signal transducer and activator of transcription (STAT), and overall decreasing transcription of proinflammatory cytokines. The clinical outcome of EMPA administration is related to improving cardiovascular risk factors, including body weight, lipid profile, blood pressure, and arterial stiffness. Intriguingly, SGLT2 suppressors can regulate microglia-driven hyperinflammation affecting neurological and cardiovascular disorders. In this review, we discuss the protective effects of EMPA in chemotherapy-induced cardiotoxicity from molecular, immunological, and neuroimmunological aspects to preclinical and clinical outcomes.
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Affiliation(s)
- Zahra Vaziri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; USERN Office, Babol University of Medical Sciences, Babol, Iran; Department of e-Learning, Virtual School of Medical Education and Management, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
| | - Cena Aram
- Department of Cell & Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Parsa Alijanizadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Ramtin Pourahmad
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Azadmehr
- Immunology Department, Babol University of Medical Sciences, Babol, Iran
| | - Naghmeh Ziaei
- Clinical Research Development unit of Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran; Department of Cardiology, Babol University of Medical Sciences, Babol, Iran.
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Takano M, Kondo H, Harada T, Takahashi M, Ishii Y, Yamasaki H, Shan T, Akiyoshi K, Shuto T, Teshima Y, Wada T, Yufu K, Sako H, Anai H, Miyamoto S, Takahashi N. Empagliflozin Suppresses the Differentiation/Maturation of Human Epicardial Preadipocytes and Improves Paracrine Secretome Profile. JACC Basic Transl Sci 2023; 8:1081-1097. [PMID: 37791312 PMCID: PMC10544075 DOI: 10.1016/j.jacbts.2023.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 10/05/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce epicardial adipose tissue (EAT) in humans, enhancing cardioprotective effects on heart failure and atrial fibrillation. We investigated the direct effect of the SGLT2 inhibitor empagliflozin on human primary epicardial adipocytes and preadipocytes. SGLT2 is primarily expressed in human preadipocytes in the EAT. The expression levels of SGLT2 significantly diminished when the preadipocytes were terminally differentiated. Adipogenesis of preadipocytes was attenuated by empagliflozin treatment without affecting cell proliferation. The messenger RNA levels and secreted protein levels of interleukin 6 and monocyte chemoattractant protein 1 were significantly decreased in empagliflozin-treated adipocytes. Coculture of human induced pluripotent stem cell-derived atrial cardiomyocytes and adipocytes pretreated with or without empagliflozin revealed that empagliflozin significantly suppressed reactive oxygen species. IL6 messenger RNA expression in human EAT showed significant clinically relevant associations. Empagliflozin suppresses human epicardial preadipocyte differentiation/maturation, likely inhibiting epicardial adipogenesis and improving the paracrine secretome profile of EAT, particularly by regulating IL6 expression.
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Affiliation(s)
- Masayuki Takano
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Hidekazu Kondo
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Taisuke Harada
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Masaki Takahashi
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Yumi Ishii
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Hirochika Yamasaki
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Tong Shan
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Kumiko Akiyoshi
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Takashi Shuto
- Department of Cardiovascular Surgery, Faculty of Medicine Oita University, Yufu-city, Oita, Japan
| | - Yasushi Teshima
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Tomoyuki Wada
- Department of Cardiovascular Surgery, Faculty of Medicine Oita University, Yufu-city, Oita, Japan
| | - Kunio Yufu
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
| | - Hidenori Sako
- Department of Cardiovascular Surgery, Oka Hospital, Oita-city, Oita, Japan
| | - Hirofumi Anai
- Department of Cardiovascular Surgery, Faculty of Medicine Oita University, Yufu-city, Oita, Japan
| | - Shinji Miyamoto
- Department of Cardiovascular Surgery, Faculty of Medicine Oita University, Yufu-city, Oita, Japan
| | - Naohiko Takahashi
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu-city, Oita, Japan
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Gorący A, Rosik J, Szostak J, Szostak B, Retfiński S, Machaj F, Pawlik A. Improving mitochondrial function in preclinical models of heart failure: therapeutic targets for future clinical therapies? Expert Opin Ther Targets 2023; 27:593-608. [PMID: 37477241 DOI: 10.1080/14728222.2023.2240021] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/19/2023] [Indexed: 07/22/2023]
Abstract
INTRODUCTION Heart failure is a complex clinical syndrome resulting from the unsuccessful compensation of symptoms of myocardial damage. Mitochondrial dysfunction is a process that occurs because of an attempt to adapt to the disruption of metabolic and energetic pathways occurring in the myocardium. This, in turn, leads to further dysfunction in cardiomyocyte processes. Currently, many therapeutic strategies have been implemented to improve mitochondrial function, but their effectiveness varies widely. AREAS COVERED This review focuses on new models of therapeutic strategies targeting mitochondrial function in the treatment of heart failure. EXPERT OPINION Therapeutic strategies targeting mitochondria appear to be a valuable option for treating heart failure. Currently, the greatest challenge is to develop new research models that could restore the disrupted metabolic processes in mitochondria as comprehensively as possible. Only the development of therapies that focus on improving as many dysregulated mitochondrial processes as possible in patients with heart failure will be able to bring the expected clinical improvement, along with inhibition of disease progression. Combined strategies involving the reduction of the effects of oxidative stress and mitochondrial dysfunction, appear to be a promising possibility for developing new therapies for a complex and multifactorial disease such as heart failure.
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Affiliation(s)
- Anna Gorący
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - Joanna Szostak
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland
| | - Bartosz Szostak
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - Szymon Retfiński
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - Filip Machaj
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
- Department of Medical Biology, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
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Samman WA, Selim SM, El Fayoumi HM, El-Sayed NM, Mehanna ET, Hazem RM. Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer's Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism. Pharmaceuticals (Basel) 2023; 16:ph16050753. [PMID: 37242536 DOI: 10.3390/ph16050753] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/02/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl3-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.
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Affiliation(s)
- Waad A Samman
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina 30078, Saudi Arabia
| | - Salma M Selim
- Department of Pharmacology and Toxicology, Faculty of Dentistry, Sinai University, Kantara, Ismailia 41636, Egypt
| | - Hassan M El Fayoumi
- Department of Pharmacology and Toxicology, Faculty of Dentistry, Sinai University, Kantara, Ismailia 41636, Egypt
| | - Norhan M El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Reem M Hazem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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10
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Huang K, Luo X, Liao B, Li G, Feng J. Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms. Cardiovasc Diabetol 2023; 22:86. [PMID: 37055837 PMCID: PMC10103501 DOI: 10.1186/s12933-023-01816-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/27/2023] [Indexed: 04/15/2023] Open
Abstract
Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy.
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Affiliation(s)
- Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Xianling Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Bin Liao
- Department of Cardiovascular Surgery, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Guang Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
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11
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Patel N, Yaqoob MM, Aksentijevic D. Cardiac metabolic remodelling in chronic kidney disease. Nat Rev Nephrol 2022; 18:524-537. [DOI: 10.1038/s41581-022-00576-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 11/09/2022]
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12
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Chen S, Coronel R, Hollmann MW, Weber NC, Zuurbier CJ. Direct cardiac effects of SGLT2 inhibitors. Cardiovasc Diabetol 2022; 21:45. [PMID: 35303888 PMCID: PMC8933888 DOI: 10.1186/s12933-022-01480-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/09/2022] [Indexed: 12/17/2022] Open
Abstract
Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) demonstrate large cardiovascular benefit in both diabetic and non-diabetic, acute and chronic heart failure patients. These inhibitors have on-target (SGLT2 inhibition in the kidney) and off-target effects that likely both contribute to the reported cardiovascular benefit. Here we review the literature on direct effects of SGLT2is on various cardiac cells and derive at an unifying working hypothesis. SGLT2is acutely and directly (1) inhibit cardiac sodium transporters and alter ion homeostasis, (2) reduce inflammation and oxidative stress, (3) influence metabolism, and (4) improve cardiac function. We postulate that cardiac benefit modulated by SGLT2i’s can be commonly attributed to their inhibition of sodium-loaders in the plasma membrane (NHE-1, Nav1.5, SGLT) affecting intracellular sodium-homeostasis (the sodium-interactome), thereby providing a unifying view on the various effects reported in separate studies. The SGLT2is effects are most apparent when cells or hearts are subjected to pathological conditions (reactive oxygen species, inflammation, acidosis, hypoxia, high saturated fatty acids, hypertension, hyperglycemia, and heart failure sympathetic stimulation) that are known to prime these plasmalemmal sodium-loaders. In conclusion, the cardiac sodium-interactome provides a unifying testable working hypothesis and a possible, at least partly, explanation to the clinical benefits of SGLT2is observed in the diseased patient.
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Affiliation(s)
- Sha Chen
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam UMC, Location Academic Medical Centre (AMC), Amsterdam, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 11, Room M0-129, Amsterdam, Noord-Holland, 1105 AZ, The Netherlands
| | - Ruben Coronel
- Department of Experimental Cardiology, Amsterdam UMC, Location Academic Medical Centre (AMC), Amsterdam,, University of Amsterdam, Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Markus W Hollmann
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam UMC, Location Academic Medical Centre (AMC), Amsterdam, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 11, Room M0-129, Amsterdam, Noord-Holland, 1105 AZ, The Netherlands
| | - Nina C Weber
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam UMC, Location Academic Medical Centre (AMC), Amsterdam, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 11, Room M0-129, Amsterdam, Noord-Holland, 1105 AZ, The Netherlands
| | - Coert J Zuurbier
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam UMC, Location Academic Medical Centre (AMC), Amsterdam, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 11, Room M0-129, Amsterdam, Noord-Holland, 1105 AZ, The Netherlands.
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13
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Sato D, Nakamura T, Amarume J, Yano M, Nishina A, Feng Z, Kusunoki M. Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load. J Pharmacol Sci 2022; 148:86-92. [PMID: 34924134 DOI: 10.1016/j.jphs.2021.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/21/2021] [Accepted: 09/27/2021] [Indexed: 12/31/2022] Open
Abstract
To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.
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Affiliation(s)
- Daisuke Sato
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan.
| | - Takao Nakamura
- Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
| | - Jota Amarume
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Mizuna Yano
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Atsuyoshi Nishina
- Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, 1-8-14 Kandasurugadai, Chiyoda-ku, 101-8308, Japan
| | - Zhonggang Feng
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Masataka Kusunoki
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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14
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Mustroph J, Hupf J, Hanses F, Evert K, Baier MJ, Evert M, Meindl C, Wagner S, Hubauer U, Pietrzyk G, Leininger S, Staudner S, Vogel M, Wallner S, Zimmermann M, Sossalla S, Maier LS, Jungbauer C. Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID-19. ESC Heart Fail 2021; 8:309-316. [PMID: 33215884 PMCID: PMC7835506 DOI: 10.1002/ehf2.13063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/09/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
AIMS We aimed to assess whether expression of whole-blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID-19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID-19 patients. METHODS AND RESULTS Whole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors. CONCLUSIONS NHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.
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Affiliation(s)
- Julian Mustroph
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Julian Hupf
- Emergency DepartmentUniversity Hospital RegensburgRegensburgGermany
| | - Frank Hanses
- Emergency DepartmentUniversity Hospital RegensburgRegensburgGermany
- Department of Infection Prevention and Infectious DiseasesUniversity Hospital RegensburgRegensburgGermany
| | - Katja Evert
- Institute of PathologyUniversity Hospital RegensburgRegensburgGermany
| | - Maria J. Baier
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Matthias Evert
- Institute of PathologyUniversity Hospital RegensburgRegensburgGermany
| | - Christine Meindl
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Stefan Wagner
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Ute Hubauer
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Gabriela Pietrzyk
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Simon Leininger
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Stephan Staudner
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Manuel Vogel
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Stefan Wallner
- Department of Clinical Chemistry and Laboratory MedicineUniversity Hospital RegensburgRegensburgGermany
| | | | - Samuel Sossalla
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Lars S. Maier
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
| | - Carsten Jungbauer
- Department of Internal Medicine II (Cardiology)University Hospital RegensburgFranz‐Josef‐Strauß‐Allee 11Regensburg93053Germany
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15
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Trum M, Riechel J, Lebek S, Pabel S, Sossalla ST, Hirt S, Arzt M, Maier LS, Wagner S. Empagliflozin inhibits Na + /H + exchanger activity in human atrial cardiomyocytes. ESC Heart Fail 2020; 7:4429-4437. [PMID: 32946200 PMCID: PMC7755005 DOI: 10.1002/ehf2.13024] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
AIMS Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na+ /H+ exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. METHODS AND RESULTS Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH4 + pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 μmol/L, 10 min). CONCLUSIONS This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.
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Affiliation(s)
- Maximilian Trum
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Johannes Riechel
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Simon Lebek
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Steffen Pabel
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Samuel T Sossalla
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Stephan Hirt
- Department of Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Michael Arzt
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Wagner
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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16
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Schubert M, Hansen S, Leefmann J, Guan K. Repurposing Antidiabetic Drugs for Cardiovascular Disease. Front Physiol 2020; 11:568632. [PMID: 33041865 PMCID: PMC7522553 DOI: 10.3389/fphys.2020.568632] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/25/2020] [Indexed: 12/13/2022] Open
Abstract
Metabolic diseases and diabetes represent an increasing global challenge for human health care. As associated with a strongly elevated risk of developing atherosclerosis, kidney failure and death from myocardial infarction or stroke, the treatment of diabetes requires a more effective approach than lowering blood glucose levels. This review summarizes the evidence for the cardioprotective benefits induced by antidiabetic agents, including sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), along with sometimes conversely discussed effects of dipeptidyl peptidase-4 inhibitor (DPP4i) and metformin in patients with high cardiovascular risk with or without type 2 diabetes. Moreover, the proposed mechanisms of the different drugs are described based on the results of preclinical studies. Recent cardiovascular outcome trials unexpectedly confirmed a beneficial effect of GLP-1RA and SGLT2i in type 2 diabetes patients with high cardiovascular risk and with standard care, which was independent of glycaemic control. These results triggered a plethora of studies to clarify the underlying mechanisms and the relevance of these effects. Taken together, the available data strongly highlight the potential of repurposing the original antidiabetics GLP1-RA and SGLT2i to improve cardiovascular outcome even in non-diabetic patients with cardiovascular diseases.
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Affiliation(s)
- Mario Schubert
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Sinah Hansen
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Julian Leefmann
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
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17
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Górriz JL, Navarro-González JF, Ortiz A, Vergara A, Nuñez J, Jacobs-Cachá C, Martínez-Castelao A, Soler MJ. Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease. Nephrol Dial Transplant 2020; 35:i13-i23. [PMID: 32003834 PMCID: PMC6993197 DOI: 10.1093/ndt/gfz237] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Indexed: 12/19/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin–angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin–angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.
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Affiliation(s)
- Jose Luis Górriz
- Hospital Clínico Universitario de Valencia, Universitat de València, INCLIVA, GEENDIAB, Valencia, Spain.,REDINREN, Madrid, Spain
| | - Juan F Navarro-González
- REDINREN, Madrid, Spain.,Unidad de Investigación y Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,Instituto de Tecnologías Biomédicas, Universidad de La Laguna, GEENDIAB, Santa Cruz de Tenerife, Spain
| | - Alberto Ortiz
- REDINREN, Madrid, Spain.,IIS-Fundación Jimenez Diaz UAM and School of Medicine, UAM, GEENDIAB, Madrid, Spain
| | - Ander Vergara
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
| | - Julio Nuñez
- Department of Cardiology, Hospital Clínico Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia, Spain.,CIBER Cardiovascular
| | - Conxita Jacobs-Cachá
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
| | | | - Maria Jose Soler
- REDINREN, Madrid, Spain.,Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
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18
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Andreadou I, Bell RM, Bøtker HE, Zuurbier CJ. SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165770. [PMID: 32194159 DOI: 10.1016/j.bbadis.2020.165770] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 12/16/2022]
Abstract
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and all-cause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial infarct size. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action (lowering intracellular Na+ and Ca2+, NHE inhibition, STAT3 and AMPK activation, CamKII inhibition, reduced inflammation and oxidative stress) that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece.
| | - Robert M Bell
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Coert J Zuurbier
- Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam Infection & Immunity, Meibergdreef 9, AZ, 1105 Amsterdam, the Netherlands.
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19
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Trum M, Wagner S, Maier LS, Mustroph J. CaMKII and GLUT1 in heart failure and the role of gliflozins. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165729. [PMID: 32068116 DOI: 10.1016/j.bbadis.2020.165729] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 02/11/2020] [Accepted: 02/12/2020] [Indexed: 12/14/2022]
Abstract
Empagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been shown to reduce mortality and hospitalization for heart failure in diabetic patients in the EMPA-REG-OUTCOME trial (Zinman et al., 2015). Surprisingly, dapagliflozin, another SGLT2 inhibitor, exerted comparable effects on clinical endpoints even in the absence of diabetes mellitus (DAPA-HF trial) (McMurray et al., 2019). There is a myriad of suggested underlying mechanisms ranging from improved glycemic control and hemodynamic effects to altered myocardial metabolism, inflammation, neurohumoral activation and intracellular ion homeostasis. Here, we review the effects of gliflozins on cardiac electro-mechanical coupling with an emphasis on novel CaMKII-mediated pathways and on cardiac glucose and ketone metabolism in the failing heart. We focus on empagliflozin as it is the gliflozin with the most abundant experimental evidence for direct effects on the heart. Where useful, we aim to compare empagliflozin to other gliflozins. To facilitate understanding of empagliflozin-induced alterations, we first give a short summary of the pathophysiological role of CaMKII in heart failure, as well as cardiac changes of glucose and ketone body metabolism in the failing heart.
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Affiliation(s)
- M Trum
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - S Wagner
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - L S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - J Mustroph
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
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20
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Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:2965. [PMID: 31426529 PMCID: PMC6720282 DOI: 10.3390/ijerph16162965] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus is a chronic metabolic disease associated with high cardiovascular (CV) risk. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the latest class of antidiabetic medication that inhibit the absorption of glucose from the proximal tubule of the kidney and hence cause glycosuria. Four SGLT2i are currently commercially available in many countries: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT2i reduce glycated hemoglobin by 0.5%-1.0% and have shown favorable effects on body weight, blood pressure, lipid profile, arterial stiffness and endothelial function. More importantly, SGLT2i have demonstrated impressive cardioprotective and renoprotective effects. The main mechanisms underlying their cardioprotective effects have been attributed to improvement in cardiac cell metabolism, improvement in ventricular loading conditions, inhibition of the Na+/H+ exchange in the myocardial cells, alteration in adipokines and cytokines production, as well as reduction of cardiac cells necrosis and cardiac fibrosis. The main adverse events of SGLT2i include urinary tract and genital infections, as well as euglycemic diabetic ketoacidosis. Concerns have also been raised about the association of SGLT2i with lower limb amputations, Fournier gangrene, risk of bone fractures, female breast cancer, male bladder cancer, orthostatic hypotension, and acute kidney injury.
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Affiliation(s)
- Anastasios Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Panayotis Vlachakis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Evangelia Tzeravini
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece.
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