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      Dapagliflozin Attenuates Myocardial Fibrosis by Inhibiting the TGF-β1/Smad Signaling Pathway in a Normoglycemic Rabbit Model of Chronic Heart Failure


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          Recent studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors play a beneficial role for normoglycemic patients with heart failure (HF). However, the underlying mechanism remains largely unexplored. In the present study, we aimed to investigate the cardioprotective effect of SGLT2 inhibitors in a normoglycemic rabbit model of chronic heart failure (CHF) and its potential mechanism was also explored. A total of 24 male New Zealand white rabbits were randomly divided into the sham group, HF group, perindopril group, and dapagliflozin (DAPA) group. The normoglycemic CHF model was established by aortic constriction for 12 weeks. In the 13th week, DAPA (1 mg/kg/day) or perindopril (0.5 mg/kg/day) was administered by oral gavage daily for 10 weeks. Both the sham group and HF group were given normal saline via gavage. After 10 weeks, the heart structure and function were evaluated by echocardiography and plasma NT-proBNP. Moreover, cardiac fibrosis was analyzed using immunohistochemistry, Masson’s trichrome staining, and Western blotting analysis. The results showed that DAPA improved the myocardial structure and function of normoglycemic CHF rabbits and ameliorated myocardial fibrosis. Further study indicated that DAPA suppressed cardiac fibrosis by inhibiting the transforming growth factor β1 (TGF-β1)/Smad signaling pathway. Collectively, our findings showed that DAPA could ameliorate cardiac fibrosis in normoglycemic CHF rabbits by inhibiting the TGF-β1/Smad signaling pathway.

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          Most cited references51

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          2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

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            Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

            The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
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              Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

              In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                13 May 2022
                : 13
                : 873108
                [1] 1 Department of Internal Medicine , Hebei Medical University , Shijiazhuang, China
                [2] 2 Department of Cardiology Center , Hebei General Hospital , Shijiazhuang, China
                Author notes

                Edited by: Antonella De Angelis, University of Campania Luigi Vanvitelli, Italy

                Reviewed by: Robert Morris Blanton, Tufts Medical Center, United States

                Evangelos-Panagiotis Daskalopoulos, European Commission, Italy

                *Correspondence: Xiaoyong Qi, xiaoyongqi2021@ 123456126.com

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2022 Chen, Yang, Bai, Yao, Liu, Xing, Meng, Qi, Dang and Qi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 10 February 2022
                : 13 April 2022
                Original Research

                Pharmacology & Pharmaceutical medicine
                sglt2 inhibition,dapagliflozin,myocardial fibrosis,chronic heart failure,rabbit model,tgfβ1/smad


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