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Gaggini M, Sabatino L, Suman AF, Chatzianagnostou K, Vassalle C. Insights into the Roles of GLP-1, DPP-4, and SGLT2 at the Crossroads of Cardiovascular, Renal, and Metabolic Pathophysiology. Cells 2025; 14:387. [PMID: 40072115 PMCID: PMC11898734 DOI: 10.3390/cells14050387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025] Open
Abstract
In recent years, new drugs for the treatment of type 2 diabetes (T2D) have been proposed, including glucagon-like peptide 1 (GLP-1) agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. Over time, some of these agents (in particular, GLP-1 agonists and SGLT2 inhibitors), which were initially developed for their glucose-lowering actions, have demonstrated significant beneficial pleiotropic effects, thus expanding their potential therapeutic applications. This review aims to discuss the mechanisms, pleiotropic effects, and therapeutic potential of GLP-1, DPP-4, and SGLT2, with a particular focus on their cardiorenal benefits beyond glycemic control.
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Affiliation(s)
- Melania Gaggini
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (L.S.)
| | - Laura Sabatino
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (L.S.)
| | - Adrian Florentin Suman
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (L.S.)
| | | | - Cristina Vassalle
- Fondazione CNR-Regione Toscana G Monasterio, Via G. Moruzzi 1, 56124 Pisa, Italy;
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Zhuang GD, Deng SM, Chen MD, Deng CF, Gu WT, Wang SM, Tang D. Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis via suppression of AGEs/RAGE/NF-κB pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118787. [PMID: 39244173 DOI: 10.1016/j.jep.2024.118787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/11/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated. AIM OF THE STUDY To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice. STUDY DESIGN AND METHODS A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice. RESULTS Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways. CONCLUSION Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.
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Affiliation(s)
- Guo-Dong Zhuang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao.
| | - Si-Min Deng
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Meng-Di Chen
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Chao-Fan Deng
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Wen-Ting Gu
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Shu-Mei Wang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Dan Tang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
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Dimitriadis K, Pitsiori D, Alexiou P, Pyrpyris N, Sakalidis A, Beneki E, Iliakis P, Tatakis F, Theofilis P, Tsioufis P, Konstantinidis D, Aggeli K, Tsioufis K. Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire? J Cardiovasc Pharmacol 2025; 85:12-20. [PMID: 39436317 DOI: 10.1097/fjc.0000000000001644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/24/2024] [Indexed: 10/23/2024]
Abstract
Heart failure (HF) has become even more prevalent in recent years, because of improved diagnostics and an increase in the risk factors predisposing to its pathology. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) emerged as one of the key pharmacotherapy options for both reduced and preserved ejection fraction, providing cardio- and renoprotection and improving mortality and cardiovascular (CV) outcomes. The pleiotropism of SGLT2i has led to multiple efforts to understand their distinct pathophysiologic interactions with various pathways, including microcirculation, endothelial dysfunction, and inflammation. More recently, the role of SGLT2i on the sympathetic nervous system (SNS) is starting to be recognized, especially because observations of retained or reduced heart rate despite volume contraction have been noted by investigators in the large clinical trials testing the safety and efficacy of these agents. Both preclinical and clinical studies have been performed, with conflicting results. Interestingly, in both settings, although there are indications of SNS modulation by SGLT2i, other studies contradict such findings, without showing, however, worsening of the autonomic homeostasis. Given the importance of neuromodulation in HF, in both pharmacologic and interventional therapies, in this review, we aim to describe the role of SNS in CV disease, focusing on HF, analyze preclinical and clinical data regarding the efficacy of SGLT2i in modulating autonomic dysfunction by examining various markers of SNS activation, and provide the most plausible theoretical backgrounds on the mechanism of benefit of SNS from the inhibition of SGLT2 receptors.
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Affiliation(s)
- Kyriakos Dimitriadis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Kansakar U, Nieves Garcia C, Santulli G, Gambardella J, Mone P, Jankauskas SS, Lombardi A. Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside. J Clin Med 2024; 13:7391. [PMID: 39685849 DOI: 10.3390/jcm13237391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.
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Affiliation(s)
- Urna Kansakar
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Crystal Nieves Garcia
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Gaetano Santulli
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Jessica Gambardella
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy
- Casa di Cura Montevergine, 83013 Mercogliano, Avellino, Italy
| | - Stanislovas S Jankauskas
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Angela Lombardi
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
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Yu Z, Lu Y, Zhang M, Lin Y, Wong TS, Guan B, Meng Y, Hu B, Liu FN, Yin L, Li Y, Zhang H, Tang D, Dai Y. Mechanism of the cardioprotective effect of empagliflozin on diabetic nephropathy mice based on the basis of proteomics. Proteome Sci 2024; 22:9. [PMID: 39427190 PMCID: PMC11490188 DOI: 10.1186/s12953-024-00232-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 09/23/2024] [Indexed: 10/21/2024] Open
Abstract
Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.
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Affiliation(s)
- Zongchao Yu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yongping Lu
- Department of Nephrology, Center of Kidney and Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Mengxian Zhang
- Department of Internal Medicine, Humen Hospital, Dongguan City, Guangdong Province, China
| | - Yanshan Lin
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Tak-Sui Wong
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Baozhang Guan
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yu Meng
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bo Hu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Fan-Na Liu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lianghong Yin
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yankun Li
- Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, China
| | - Han Zhang
- Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, China.
| | - Donge Tang
- Clinical Medical Research Center, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, 518020, China.
| | - Yong Dai
- The First Affiliated Hospital, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China.
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Liu DD, Liu XL, Zheng TF, Li X, Zhao YC, Pan JC, Yuan C, Wang QQ, Zhang M. Dapagliflozin alleviates right heart failure by promoting collagen degradation by reducing ROS levels. Eur J Pharmacol 2024; 981:176875. [PMID: 39121982 DOI: 10.1016/j.ejphar.2024.176875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. METHODS We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA. RESULTS In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. CONCLUSIONS In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.
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Affiliation(s)
- Dong-Dong Liu
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao-Lin Liu
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Teng-Fei Zheng
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Li
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Ya-Chao Zhao
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Ji-Chen Pan
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Chong Yuan
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Qian-Qian Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, No.1677 Wutai Mountain Road, Qingdao, 266000, China.
| | - Mei Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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Liu W, You D, Lin J, Zou H, Zhang L, Luo S, Yuan Y, Wang Z, Qi J, Wang W, Ye X, Yang X, Deng Y, Teng F, Zheng X, Lin Y, Huang Z, Huang Y, Yang Z, Zhou X, Zhang Y, Chen R, Xu L, Li J, Yang W, Zhang H. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8 + T cell activation. Cell Metab 2024; 36:2245-2261.e6. [PMID: 39243758 DOI: 10.1016/j.cmet.2024.08.005] [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: 01/23/2023] [Revised: 02/26/2024] [Accepted: 08/09/2024] [Indexed: 09/09/2024]
Abstract
During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.
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Affiliation(s)
- Wenhui Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Danming You
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayang Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huren Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shenjian Luo
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youwen Yuan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiyi Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Qi
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xueru Ye
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyu Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yajuan Deng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Teng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojun Zheng
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yuhao Lin
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiwei Huang
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan Huang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhi Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Zhou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanan Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruxin Chen
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingling Xu
- Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jin Li
- Division of Endocrinology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, China.
| | - Wei Yang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Key Laboratory of Cell Metabolic Homeostasis and Major Chronic Diseases, Guangzhou, China.
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8
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Galli F, Bartolini D, Ronco C. Oxidative stress, defective proteostasis and immunometabolic complications in critically ill patients. Eur J Clin Invest 2024; 54:e14229. [PMID: 38676423 DOI: 10.1111/eci.14229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/31/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024]
Abstract
Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro-oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes-macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness.
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Affiliation(s)
- Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Desirée Bartolini
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Claudio Ronco
- Department of Medicine, International Renal Research Institute of Vicenza, University of Padova, San Bortolo Hospital Vicenza, Vicenza, Italy
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Li Y, Zhang Z, Zhang Z, Zheng N, Ding X. Empagliflozin, a sodium-glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome. J Cell Physiol 2024; 239:e31264. [PMID: 38764242 DOI: 10.1002/jcp.31264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 05/21/2024]
Abstract
Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.
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Affiliation(s)
- Yunhao Li
- Graduate School, China Medical University, Shenyang, China
- Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China
| | - Zhanming Zhang
- Faculty of Science, The University of Hong Kong, Hong Kong, China
| | - Zheming Zhang
- Graduate School, China Medical University, Shenyang, China
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Ningning Zheng
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Xudong Ding
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
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Li Y, Lou N, Liu X, Zhuang X, Chen S. Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction. Biomed Pharmacother 2024; 175:116755. [PMID: 38772155 DOI: 10.1016/j.biopha.2024.116755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/23/2024] Open
Abstract
With the increasing prevalence of type 2 diabetes mellitus (T2DM), it has become critical to identify effective treatment strategies. In recent years, the novel oral hypoglycaemic drug Imeglimin has attracted much attention in the field of diabetes treatment. The mechanisms of its therapeutic action are complex and are not yet fully understood by current research. Current evidence suggests that pancreatic β-cells, liver, and skeletal muscle are the main organs in which Imeglimin lowers blood glucose levels and that it acts mainly by targeting mitochondrial function, thereby inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, promoting pancreatic β-cell function, and regulating energy metabolism. There is growing evidence that the drug also has a potentially volatile role in the treatment of diabetic complications, including metabolic cardiomyopathy, diabetic vasculopathy, and diabetic neuroinflammation. According to available clinical studies, its efficacy and safety profile are more evident than other hypoglycaemic agents, and it has synergistic effects when combined with other antidiabetic drugs, and also has potential in the treatment of T2DM-related complications. This review aims to shed light on the latest research progress in the treatment of T2DM with Imeglimin, thereby providing clinicians and researchers with the latest insights into Imeglimin as a viable option for the treatment of T2DM.
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Affiliation(s)
- Yilin Li
- Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China
| | - Nenngjun Lou
- Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China
| | - Xiaojing Liu
- Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China
| | - Xianghua Zhuang
- Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan 250033, China.
| | - Shihong Chen
- Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University, Jinan 250033, China.
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Annoni F, Gouvea Bogossian E, Peluso L, Su F, Moreau A, Nobile L, Casu SG, Sterchele ED, Calabro L, Salvagno M, Oddo M, Taccone FS. Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use. Cells 2024; 13:784. [PMID: 38727320 PMCID: PMC11083685 DOI: 10.3390/cells13090784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/27/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024] Open
Abstract
Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.
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Affiliation(s)
- Filippo Annoni
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
| | - Elisa Gouvea Bogossian
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
| | - Lorenzo Peluso
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Department of Anesthesiology and Intensive Care, Humanitas Gavazzeni Hospital, 24125 Bergamo, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Fuhong Su
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
| | - Anthony Moreau
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
| | - Leda Nobile
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
| | - Stefano Giuseppe Casu
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
| | - Elda Diletta Sterchele
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
| | - Lorenzo Calabro
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
| | - Michele Salvagno
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
| | - Mauro Oddo
- Medical Directorate for Research, Education and Innovation, Direction Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, 1011 Lausanne, Switzerland
| | - Fabio Silvio Taccone
- Department of Intensive Care, University Hospital of Brussels (HUB), 1070 Brussels, Belgium
- Experimental Laboratory of Intensive Care, Department of Intensive Care, Free University of Brussels (ULB), 1070 Brussels, Belgium
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12
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Zandifar A, Panahi M, Badrfam R, Qorbani M. Efficacy of empagliflozin as adjunctive therapy to citalopram in major depressive disorder: a randomized double-blind, placebo-controlled clinical trial. BMC Psychiatry 2024; 24:163. [PMID: 38408937 PMCID: PMC10895773 DOI: 10.1186/s12888-024-05627-0] [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: 09/03/2023] [Accepted: 02/20/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND Major depressive disorder is one of the most common psychiatric disorders, which is associated with a high disease burden. Current treatments using antidepressants have limitations, so using medication with neuromodulating and anti-inflammatory properties alongside them could be helpful. In a clinical trial, we studied the effectiveness of empagliflozin, a blood sugar-lowering drug, as an adjunctive therapy to reduce the severity of depression symptoms. METHODS A number of outpatients with moderate to severe depression (Hamilton Depression Rating Scale (HDRS) > = 17) who were not under related medication or had not taken medication for at least the last two months, had an age range of 18-60 years and had written informed consent to enter the study (N = 90) were randomly divided into two groups receiving placebo or empagliflozin (10 mg daily) combined with citalopram (40 mg daily) based on permuted block randomization method in an 8-week randomized, double-blind, placebo-controlled clinical trial. They were evaluated using the HDRS in weeks 0, 4, and 8. RESULTS HDRS scores were equal to 28.42(± 3.83), 20.20(± 3.82), and 13.42(± 3.42) in the placebo group during weeks 0,4, and 8, respectively. These scores were 27.36(± 3.77), 13.76(± 1.40), and 7.00(± 1.13), respectively, for the group treated with empagliflozin. Compared to the control group, patients treated with empagliflozin using repeated-measures ANOVA showed greater improvement in reducing the severity of depression symptoms over time (p value = 0.0001). CONCLUSIONS Considering the promising findings in this clinical trial, further study of empagliflozin as adjunctive therapy in MDD with larger sample sizes and longer follow-ups is recommended.
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Affiliation(s)
- Atefeh Zandifar
- Social Determinants of Health Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Department of Psychiatry, Imam Hossein Hospital, Alborz University of Medical Sciences, Karaj, Alborz, Iran
| | - Maryam Panahi
- Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Rahim Badrfam
- Department of Psychiatry, Imam Hossein Hospital, Alborz University of Medical Sciences, Karaj, Alborz, Iran.
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Chronic Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Li N, Zhu QX, Li GZ, Wang T, Zhou H. Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway. World J Diabetes 2023; 14:1862-1876. [PMID: 38222788 PMCID: PMC10784799 DOI: 10.4239/wjd.v14.i12.1862] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/20/2023] [Accepted: 11/17/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear. AIM To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism. METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels. RESULTS In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes. CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
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Affiliation(s)
- Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Qiu-Xiao Zhu
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Gui-Zhi Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Axelsen JS, Nielsen-Kudsk AH, Schwab J, Ringgaard S, Nielsen-Kudsk JE, de Man FS, Andersen A, Andersen S. Effects of empagliflozin on right ventricular adaptation to pressure overload. Front Cardiovasc Med 2023; 10:1302265. [PMID: 38162132 PMCID: PMC10757621 DOI: 10.3389/fcvm.2023.1302265] [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: 09/26/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
Background Right ventricular (RV) failure is the prime cause of death in patients with pulmonary arterial hypertension. Novel treatment strategies that protect the RV are needed. Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, shows cardioprotective effects on the left ventricle in clinical and preclinical studies, but its direct effects on RV remain elusive. We investigated the effects of empagliflozin on RV dysfunction induced by pulmonary trunk banding (PTB). Methods Male Wistar rats (116 ± 10 g) were randomized to PTB or sham surgery. One week after surgery, PTB animals received empagliflozin mixed into the chow (300 mg empagliflozin/kg chow; PTB-empa, n = 10) or standard chow (PTB-control, n = 10). Sham rats (Sham, n = 6) received standard chow. After five weeks, RV function was evaluated by echocardiography, cardiac MRI, and invasive pressure-volume measurements. Results PTB caused RV failure evident by decreased cardiac output compared with sham. PTB-empa rats had a 49% increase in water intake compared with PTB-control yet no differences in hematocrit or blood glucose. Treatment with empagliflozin decreased RV end-systolic pressures without any changes in RV cardiac output or ventricular-arterial coupling (Ees/Ea). The decrease in RV end-systolic pressure was complemented by a slight reduction in RV cross sectional area as a sign of reduced hypertrophy. Load-independent measures of RV systolic and diastolic function were not affected in PTB-empa rats compared with PTB-control. Conclusion Empagliflozin treatment reduced RV end-systolic pressure in RV failure induced by pressure overload. Further studies are needed to elucidate whether this simply relates to a diuretic effect and/or additional independent beneficial RV effects.
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Affiliation(s)
- Julie S. Axelsen
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Anders H. Nielsen-Kudsk
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Janne Schwab
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Jens Erik Nielsen-Kudsk
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Frances S. de Man
- PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Locatie VUmc, Amsterdam, Netherlands
| | - Asger Andersen
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Stine Andersen
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Su S, Ji X, Li T, Teng Y, Wang B, Han X, Zhao M. The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy. Front Cardiovasc Med 2023; 10:1291450. [PMID: 38124893 PMCID: PMC10731052 DOI: 10.3389/fcvm.2023.1291450] [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: 09/09/2023] [Accepted: 11/13/2023] [Indexed: 12/23/2023] Open
Abstract
Background/aims To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism. Methods A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality. Results The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i. Conclusion SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases. Systematic review registration https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).
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Affiliation(s)
- Sha Su
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiang Ji
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Tong Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yu Teng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Baofu Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiaowan Han
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Department of Cardiology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Mingjing Zhao
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
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16
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Lyu Y, Huo J, Jiang W, Yang W, Wang S, Zhang S, Cheng Y, Jiang Z, Shan Q. Empagliflozin ameliorates cardiac dysfunction in heart failure mice via regulating mitochondrial dynamics. Eur J Pharmacol 2023; 942:175531. [PMID: 36690056 DOI: 10.1016/j.ejphar.2023.175531] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
Empagliflozin has cardioprotective effects in patients with heart failure (HF). However, the mechanism by which empagliflozin protects against HF remains controversial. Study aimed to evaluate the effect of empagliflozin on myocardial fibrosis and cardiac function in HF mice and its possible mechanism. C57BL/6 mice were induced with HF by ligation of the left anterior descending coronary artery. At 4 weeks postoperation, mice were randomly given normal saline or empagliflozin for 8 weeks. Echocardiography was used to assess cardiac function. Masson's staining, immunohistochemistry and Western blot analysis were used to detect the degree of myocardial fibrosis. Changes in mitochondria were detected by observing mitochondrial morphology, measuring mitochondrial dynamics-related proteins and analysing the levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP). The mitochondrial fission inhibitor, mdivi1, was used to detect the relationship between mitochondrial dysfunction and cardiac dysfunction in HF mice. HF led to myocardial fibrosis and cardiac dysfunction. However, treatment with empagliflozin reduced these effects. Empagliflozin inhibited mitochondrial fission and improved energy metabolic efficiency in HF mice by regulating the expression of mitochondrial dynamics-related proteins. Similarly, mdivi1 attenuated mitochondrial dysfunction and cardiac dysfunction by inhibiting mitochondrial fission in HF mice. Regulation of mitochondrial dynamics, especially inhibition of mitochondrial fission, may be a potential target for reducing cardiac damage in patients with HF. Empagliflozin improved myocardial fibrosis and cardiac dysfunction by modulating mitochondrial dynamics in HF mice. Thus, the cardiac protective effect of empagliflozin may be related to the normalization of mitochondria and the increase in ATP production.
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Affiliation(s)
- YiTing Lyu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - JunYu Huo
- Department of Cardiology, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - WanYing Jiang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wen Yang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - ShengChan Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - ShiGeng Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - YanDi Cheng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - ZhiXin Jiang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - QiJun Shan
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Cai C, Wu F, Zhuang B, Ou Q, Peng X, Shi N, Peng L, Li Z, Wang J, Cai S, Tan Y. Empagliflozin activates Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome. Mol Metab 2022; 64:101553. [PMID: 35863636 PMCID: PMC9372775 DOI: 10.1016/j.molmet.2022.101553] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/10/2022] [Accepted: 07/14/2022] [Indexed: 12/04/2022] Open
Abstract
Objectives Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3. Methods Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CKO) mice were subjected to CRS-3 prior to assessment of mitochondrial homeostasis in the presence or absence of empagliflozin. Results CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated β-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a β-catenin inhibitor reversed these effects. Conclusions In summary, empagliflozin activated Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.
Empagliflozin reduces myocardial damage and improves myocardial function after CRS-3. Empagliflozin normalizes the mitochondrial structure in cardiomyocytes during CRS-3. Empagliflozin attenuates cardiomyocyte mitochondrial dysfunction during CRS-3. Empagliflozin activates FUNDC1-dependent mitophagy and preserves mitochondrial integrity in the heart during CRS-3. Loss of FUNDC1 abolishes the cardioprotective effects of empagliflozin during CRS-3.
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Affiliation(s)
- Chen Cai
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Feng Wu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Bingjie Zhuang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qing Ou
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xiaojie Peng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Nengxian Shi
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Lan Peng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ziying Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jin Wang
- Department of Vascular Medicine, Peking University Shougang Hospital, Beijing 100144, China.
| | - Shumin Cai
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
| | - Ying Tan
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
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18
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Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7736416. [PMID: 35847595 PMCID: PMC9283010 DOI: 10.1155/2022/7736416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022]
Abstract
Ketone bodies including β-hydroxybutyrate (β-HB) have been proved the therapeutic potential in diverse neurological disorders. However, the role of β-HB in the regulation of neurological injury after cardiac arrest (CA) remains unclear. We investigated the effect of β-HB on brain mitochondrial dysfunction and neurological function after CA. A rat model of CA was established by asphyxia. The rats were randomly divided into three groups: sham group, control group, and β-HB group. Animals received 200 mg/kg β-HB or same volume vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Neurological function was evaluated by neurologic deficit score and Y-maze. Neuronal cell loss and apoptosis were detected through hematoxylin-eosin staining, Nissl staining, and TdT-mediated dUTP nick-end labeling assay. Oxidative stress levels were determined by immunohistochemical staining of 4-hydoxynonenal and 8-hydroxy-2′-deoxyguanosine. Furthermore, mitochondrial ultrastructure of brain cells was observed by transmission electron microscopy. In addition, the protein expression levels of Bak, caspase 3, gasdermin D, caspase 1, brain-derived neurotrophic factor, dynamin-related protein 1 (Drp1), and phospho-Drp1 (ser616) were measured. We found that neurological function and survival rate were significantly higher in the β-HB group compared with the control group. β-HB also reduced neurons death and neurological oxidative stress after CA. Moreover, β-HB reduced neurological injury from apoptosis and pyroptosis after CA. In addition, β-HB maintained the structural integrity of brain mitochondria, prevented mitochondrial fission, and increased brain energy metabolism after CA. In conclusion, β-HB beneficially affected the neurological function of rats after global cerebral ischemia, associated with decreased mitochondrial fission, and improved mitochondrial function. Our results suggest that β-HB might benefit patients suffering from neurological dysfunction after CA.
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19
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Zou R, Shi W, Qiu J, Zhou N, Du N, Zhou H, Chen X, Ma L. Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis. Cardiovasc Diabetol 2022; 21:106. [PMID: 35705980 PMCID: PMC9202214 DOI: 10.1186/s12933-022-01532-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/25/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Empagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role of empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) has not been fully understood. METHODS Electron microscopy, western blots, immunofluorescence, qPCR, mutant plasmid transfection, co-immunoprecipitation were employed to explore whether empagliflozin could alleviate microvascular damage and endothelial injury during cardiac I/R injury. RESULTS In mice, empagliflozin attenuated I/R injury-induced microvascular occlusion and microthrombus formation. In human coronary artery endothelial cells, I/R injury led to adhesive factor upregulation, endothelial nitric oxide synthase inactivation, focal adhesion kinase downregulation, barrier dysfunction, cytoskeletal degradation and cellular apoptosis; however, empagliflozin treatment diminished these effects. Empagliflozin improved mitochondrial oxidative stress, mitochondrial respiration and adenosine triphosphate metabolism in I/R-treated human coronary artery endothelial cells by preventing the phosphorylation of dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1), thus repressing mitochondrial fission. The protective effects of empagliflozin on mitochondrial homeostasis and endothelial function were abrogated by the re-introduction of phosphorylated Fis1, but not phosphorylated Drp1, suggesting that Fis1 dephosphorylation is the predominant mechanism whereby empagliflozin inhibits mitochondrial fission during I/R injury. Besides, I/R injury induced Fis1 phosphorylation primarily by activating the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) pathway, while empagliflozin inactivated this pathway by exerting anti-oxidative effects. CONCLUSIONS These results demonstrated that empagliflozin can protect the microvasculature by inhibiting the DNA-PKcs/Fis1/mitochondrial fission pathway during myocardial I/R injury.
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Affiliation(s)
- Rongjun Zou
- Heart Center, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Wanting Shi
- Department of Paediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.,Child Healthcare Department, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Junxiong Qiu
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Na Zhou
- Child Healthcare Department, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.,Department of extracorporeal circulation, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Na Du
- Department of Nursing, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Hao Zhou
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, 100048, Beijing, China. .,Department of Cardiology, Chinese PLA General Hospital, Medical School of Chinese PLA, 100037, Beijing, China.
| | - Xinxin Chen
- Heart Center, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Li Ma
- Heart Center, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
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20
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Mitochondria-Mediated Cardiovascular Benefits of Sodium-Glucose Co-Transporter 2 Inhibitors. Int J Mol Sci 2022; 23:ijms23105371. [PMID: 35628174 PMCID: PMC9140946 DOI: 10.3390/ijms23105371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 11/23/2022] Open
Abstract
Several recent cardiovascular trials of SGLT 2 (sodium-glucose cotransporter 2) inhibitors revealed that they could reduce adverse cardiovascular events in patients with T2DM (type 2 diabetes mellitus). However, the exact molecular mechanism underlying the beneficial effects that SGLT2 inhibitors have on the cardiovascular system is still unknown. In this review, we focus on the molecular mechanisms of the mitochondria-mediated beneficial effects of SGLT2 inhibitors on the cardiovascular system. The application of SGLT2 inhibitors ameliorates mitochondrial dysfunction, dynamics, bioenergetics, and ion homeostasis and reduces the production of mitochondrial reactive oxygen species, which results in cardioprotective effects. Herein, we present a comprehensive overview of the impact of SGLT2 inhibitors on mitochondria and highlight the potential application of these medications to treat both T2DM and cardiovascular diseases.
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21
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Wang X, Wang Z, Liu D, Jiang H, Cai C, Li G, Yu G. Canagliflozin Prevents Lipid Accumulation, Mitochondrial Dysfunction, and Gut Microbiota Dysbiosis in Mice With Diabetic Cardiovascular Disease. Front Pharmacol 2022; 13:839640. [PMID: 35281938 PMCID: PMC8905428 DOI: 10.3389/fphar.2022.839640] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is associated with cardiovascular disease (CVD) and sodium glucose cotransporter 2 inhibitors, as oral medications for T2DM treatment have shown the potential to improve vascular dysfunction. The aim of this study was to evaluate the ability of canagliflozin (Cana) to relieve CVD in T2DM mice and its possible action mechanism. Mice with diabetic CVD was conducted by a high-fat diet for 24 weeks, followed by oral gavaging with metformin (200 mg/kg/day) or Cana (50 mg/kg/day) for 6 weeks. The result demonstrated that Cana reduced serum lipid accumulation, and decreased the arteriosclerosis index and atherogenic index of plasma. In addition, Cana treatment reduced the circulating markers of inflammation. More importantly, Cana improved cardiac mitochondrial homeostasis and relieved oxidative stress. Moreover, Cana treatment alleviated the myocardial injury with decreasing levels of serous soluble cluster of differentiation 40 ligand and cardiac troponin I. Thus, cardiovascular abnormality was relieved by suppressing fibrosis and basement membrane thickening, while elevating the cluster of differentiation 31 expression level. Importantly, Cana increased the ratio of gut bacteria Firmicutes/Bacteroidetes and the relative abundance of Alistipes, Olsenella, and Alloprevotella, while it decreased the abundance of Mucispirillum, Helicobacter, and Proteobacteria at various taxonomic levels in mice with diabetic CVD. In short, Cana treatment altered the colonic microbiota composition close to the normal level, which was related with blood lipid, inflammation, and oxidative stress, and might play a vital role in CVD. In general, the improvements in the gut microbiota and myocardial mitochondrial homeostasis may represent the mechanism of Cana on CVD treatment.
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Affiliation(s)
- Xueliang Wang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, China
| | - Zhe Wang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Di Liu
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Hao Jiang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chao Cai
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, China
| | - Guoyun Li
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, China
| | - Guangli Yu
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, China
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22
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Short-Chain Carbon Sources. JACC Basic Transl Sci 2022; 7:730-742. [PMID: 35958686 PMCID: PMC9357564 DOI: 10.1016/j.jacbts.2021.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 11/24/2022]
Abstract
Heart failure (HF) remains the leading cause of morbidity and mortality in the developed world, highlighting the urgent need for novel, effective therapeutics. Recent studies support the proposition that improved myocardial energetics as a result of ketone body (KB) oxidation may account for the intriguing beneficial effects of sodium-glucose cotransporter-2 inhibitors in patients with HF. Similar small molecules, short-chain fatty acids (SCFAs) are now realized to be preferentially oxidized over KBs in failing hearts, contradicting the notion of KBs as a rescue "superfuel." In addition to KBs and SCFAs being alternative fuels, both exert a wide array of nonmetabolic functions, including molecular signaling and epigenetics and as effectors of inflammation and immunity, blood pressure regulation, and oxidative stress. In this review, the authors present a perspective supported by new evidence that the metabolic and unique nonmetabolic activities of KBs and SCFAs hold promise for treatment of patients with HF with reduced ejection fraction and those with HF with preserved ejection fraction.
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23
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Song Y, Huang C, Sin J, Germano JDF, Taylor DJR, Thakur R, Gottlieb RA, Mentzer RM, Andres AM. Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis. Int J Mol Sci 2021; 23:437. [PMID: 35008865 PMCID: PMC8745294 DOI: 10.3390/ijms23010437] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/23/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.
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Affiliation(s)
- Yang Song
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Chengqun Huang
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Jon Sin
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
- University of Alabama, Birmingham, AL 35294, USA
| | - Juliana de F. Germano
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - David J. R. Taylor
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Reetu Thakur
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Roberta A. Gottlieb
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Robert M. Mentzer
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Allen M. Andres
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
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