Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Dec 15, 2023; 14(12): 1862-1876
Published online Dec 15, 2023. doi: 10.4239/wjd.v14.i12.1862
Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway
Na Li, Qiu-Xiao Zhu, Gui-Zhi Li, Ting Wang, Hong Zhou
Na Li, Qiu-Xiao Zhu, Gui-Zhi Li, Ting Wang, Hong Zhou, Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Author contributions: Li N, Zhu QX, Li GZ, Wang T, and Zhou H designed and coordinated the study; Li N, Zhu QX, Li GZ, and Zhou H performed the experiments, and acquired and analyzed the data; Li N interpreted the data; Li N and Zhou H wrote the manuscript; all authors approved the final version of the article.
Supported by Health Commission of Hebei Province, No. 20210196; S & T Program of Hebei, No. 22377726D.
Institutional review board statement: The study was reviewed and approved by the research ethics committee of the Second Hospital of Hebei Medical University Institutional Review Board (Approval No. 2022-AE136).
Conflict-of-interest statement: The authors declare no competing interests for this article.
Data sharing statement: The data of this study are available from the corresponding authors upon request.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong Zhou, PhD, Chief Physician, Doctor, Department of Endocrinology, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang 050000, Hebei Province, China. zhoubs2013@163.com
Received: September 21, 2023
Peer-review started: September 21, 2023
First decision: October 10, 2023
Revised: October 20, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 15, 2023
Processing time: 83 Days and 20.1 Hours
ARTICLE HIGHLIGHTS
Research background

Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure in diabetic patients. However, there is no specific therapy to delay the progression of DCM. Empagliflozin has been confirmed to reduce the risk of hospitalization for heart failure in diabetic patients. However, the molecular mechanisms by which these agents exert cardioprotection remain unclear.

Research motivation

To explore the effects of empagliflozin on the development of DCM.

Research objectives

To investigate whether empagliflozin can improve mitochondrial injury and cardiac dysfunction, and prevent high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis, along with the underlying molecular mechanism.

Research methods

We used db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) separately as in vivo and in vitro models. Cardiac function was evaluated by echocardiography. We used transmission electron microscopy to observe mitochondrial injury. RT-qPCR, Western blot, flow cytometry, TdT-mediated dUTP-biotin nick end labeling staining, and immunofluorescence were used to investigate the effects of empagliflozin treatment on cellular processes in cardiomyocytes of neonatal rats stimulated with HG.

Research results

Empagliflozin significantly improved cardiac dysfunction and dramatically reduced myocardial apoptosis, accompanied by upregulation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), as well as downregulation of myosin phosphatase target subunit 1 (MYPT1) in the heart of mice. At the cellular level, treatment of cardiomyocytes with empagliflozin or FA (a ROCK inhibitor) or overexpression of PGC-1α all markedly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, AMPK inhibitor reversed the above effects in part. Furthermore, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes.

Research conclusions

Empagliflozin improves mitochondrial injury and cardiac dysfunction in db/db mice, and prevents HG-induced oxidative stress and cardiomyocyte apoptosis in vitro at least partially by activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway independent of SGLT2.

Research perspectives

Next step, we will establish a positive drug control in vivo and further clarify the effects of empagliflozin on DCM, with an objective of providing a new strategy for the prevention and treatment of DCM.