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      Dapagliflozin attenuates cardiac remodeling and dysfunction in rats with β-adrenergic receptor overactivation through restoring calcium handling and suppressing cardiomyocyte apoptosis

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          Abstract

          Background: Long-term β-adrenergic receptor (β-AR) activation can impair myocardial structure and function. Dapagliflozin (DAPA) has been reported to improve clinical prognosis in heart failure patients, whereas the exact mechanism remains unclear. Here, we investigated the effects of DAPA against β-AR overactivation toxicity and explored the underlying mechanism.

          Methods and Results: Rats were randomized to receive saline + placebo, isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) + placebo, or ISO + DAPA (1 mg/kg/day, intragastrically) for 2-week. DAPA treatment improved cardiac function, alleviated myocardial fibrosis, prevented cardiomyocytes (CMs) apoptosis, and decreased the expression of ER stress-mediated apoptosis markers in ISO-treated hearts. In isolated CMs, 2-week ISO stimulation resulted in deteriorated kinetics of cellular contraction and relaxation, increased diastolic intracellular Ca 2+ level and decay time constant of Ca 2+ transient (CaT) but decreased CaT amplitude and sarcoplasmic reticulum (SR) Ca 2+ level. However, DAPA treatment prevented abnormal Ca 2+ handling and contractile dysfunction in CMs from ISO-treated hearts. Consistently, DAPA treatment upregulated the expression of SR Ca 2+-ATPase protein and ryanodine receptor 2 (RyR2) but reduced the expression of phosphorylated-RyR2, Ca 2+/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated-CaMKII in ventricles from ISO-treated rats.

          Conclusion: DAPA prevented myocardial remodeling and cardiac dysfunction in rats with β-AR overactivation via restoring calcium handling and suppressing ER stress-related CMs apoptosis.

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          Most cited references47

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          Cardiac excitation-contraction coupling.

          Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important. It is crucial to the very process that enables the chambers of the heart to contract and relax, a process called excitation-contraction coupling. It is important to understand in quantitative detail exactly how calcium is moved around the various organelles of the myocyte in order to bring about excitation-contraction coupling if we are to understand the basic physiology of heart function. Furthermore, spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
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            Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes

            Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes.
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              Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats.

              The inhibition of gut and renal sodium-glucose cotransporters (SGLTs) has been proposed as a novel therapeutic approach to the treatment of diabetes. We have identified dapagliflozin as a potent and selective inhibitor of the renal sodium-glucose cotransporter SGLT2 in vitro and characterized its in vitro and in vivo pharmacology. Cell-based assays measuring glucose analog uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Acute and multi-dose studies in normal and diabetic rats were performed to assess the ability of dapagliflozin to improve fed and fasting plasma glucose levels. A hyperinsulinemic-euglycemic clamp study was performed to assess the ability of dapagliflozin to improve glucose utilization after multi-dose treatment. Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitative glucose transport in human adipocytes. In vivo, dapagliflozin acutely induced renal glucose excretion in normal and diabetic rats, improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats after single oral doses ranging from 0.1 to 1.0 mg/kg. Once-daily dapagliflozin treatment over 2 weeks significantly lowered fasting and fed glucose levels at doses ranging from 0.1 to 1.0 mg/kg and resulted in a significant increase in glucose utilization rate accompanied by a significant reduction in glucose production. These data suggest that dapagliflozin has the potential to be an efficacious treatment for type 2 diabetes.
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                Author and article information

                Journal
                Diab Vasc Dis Res
                Diab Vasc Dis Res
                spdvr
                DVR
                Diabetes & Vascular Disease Research
                SAGE Publications (Sage UK: London, England )
                1479-1641
                1752-8984
                17 August 2023
                Jul-Aug 2023
                : 20
                : 4
                : 14791641231197106
                Affiliations
                [1 ]Department of Cardiology, Ringgold 117921, universityRenmin Hospital of Wuhan University; , Wuhan, China
                [2 ]Cardiovascular Research Institute, universityWuhan University; , Wuhan, China
                [3 ]universityHubei Key Laboratory of Cardiology; , Wuhan, China
                [4 ]Department of Cardiology, Ringgold 159433, universityQinghai Provincial People's Hospital; , Xining, China
                [5 ]Montreal Heart Institute (MHI), Department of Medicine, Faculty of Medicine, Ringgold 5622, universityUniversité de Montréal; , Montreal, QC, Canada
                Author notes
                [*]Tao Liu, Department of Cardiology, Renmin Hospital of Wuhan University, zhangzhidong road 99, Wuhan, 430060, China. Email: taoliu@ 123456whu.edu.cn
                Jingchun Wu, Department of Cardiology, Qinghai Provincial People's Hospital, No.2 Gong He Road, Xining 810007, China. Email: wujinchun117@ 123456sina.com
                Shaobo Shi, Department of Cardiology, Renmin Hospital of Wuhan University, Zhangzhidong Road 99, Wuhan 430060, China. Email: shiyige@ 123456whu.edu.cn
                Author information
                https://orcid.org/0009-0006-6626-9813
                Article
                10.1177_14791641231197106
                10.1177/14791641231197106
                10437211
                37589258
                83e69890-52dc-4c3a-88bf-a5d3aa70603a
                © The Author(s) 2023

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Funding
                Funded by: National Natural Science Foundation of China, FundRef https://doi.org/10.13039/501100001809;
                Award ID: 82270365
                Funded by: the Application and Basic Research Project from the Science and Technology Department of Qinghai Province;
                Award ID: Grant No. 2022-ZJ-758
                Categories
                Original Article
                Custom metadata
                ts10
                July-August 2023

                Endocrinology & Diabetes
                dapagliflozin,β-adrenergic receptor,cardiac function,myocardial fibrosis,apoptosis,calcium handling

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