Empagliflozin Attenuates Cardiac Dysfunction in Rat Model of Metabolic Syndrome: Evaluating Role of the Cardiac Renin–Angiotensin System

Q: What are the key findings of this study?

Empagliflozin significantly improved ejection fraction compared to vehicle in rats with metabolic syndrome (77.67% vs 69.16%, p=0.0002).

Q: What is the clinical evidence from this study?

Population: Metabolic Syndrome (n=24). Intervention: Empagliflozin vs. Vehicle. Primary outcome: Ejection fraction (p=0.0002).

Q: What does this research mean for the field?

Empagliflozin attenuates cardiac dysfunction in metabolic syndrome by modulating local cardiac Renin-Angiotensin System components, specifically the pERK1/2–NHE1–NCX signaling pathway, and reducing oxidative stress and inflammation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Reihaneh Ghasemi Tarie; Alireza Esteghamati; Kamran Rakhshan; Sadaf Esteghamati; Mansoor Keshavarz

doi:10.3390/biomedicines14071533

July 8, 2026BiomedicinesOpen Access

Empagliflozin Attenuates Cardiac Dysfunction in Rat Model of Metabolic Syndrome: Evaluating Role of the Cardiac Renin–Angiotensin System

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Key result

Empagliflozin improves LVEF ~12% vs vehicle in rats with metabolic syndrome.

P=0.0002
n=24

Why the study?

Empagliflozin modulates local renin-angiotensin system components in the kidney and liver, but its role in regulating cardiac renin-angiotensin system in cardiometabolic syndrome needed further study.

Does empagliflozin improve cardiac function and modulate the local cardiac RAS in a rat model of metabolic syndrome?

Key Points

To assess whether empagliflozin attenuates cardiac dysfunction and modulates local cardiac renin–angiotensin system components and related downstream signaling pathways in metabolic syndrome.
Twenty-four male Wistar rats were divided into control and high-fat diet-induced metabolic syndrome groups for 8 weeks, followed by treatment of half of each group with empagliflozin (10 mg/kg) for 8 additional weeks.
Evaluated fasting blood sugar, lipid profiles, and cardiac function via echocardiography, followed by Western blot analysis of left ventricular RAS components (AngII, AT1R, AT2R) and downstream effectors (pERK1/2, NHE1, NCX, NLRP3) and ROS quantification by ELISA.
Empagliflozin treatment significantly reduced weight gain (-17.20 ± 11.70 vs. 57.40 ± 8.20, p < 0.0001), decreased fasting blood sugar (121.30 ± 7.22 vs. 248.19 ± 19.36, p < 0.0001), lowered TG (50.26 ± 5.63 vs. 85.20 ± 5.90, p = 0.0011) and LDL-C (21.80 ± 1.61 vs. 30.58 ± 2.17, p = 0.0042), and increased HDL-C (39.42 ± 1.72 vs. 29.33 ± 1.91, p = 0.002).
Cardiac function improved markedly with empagliflozin relative to untreated metabolic syndrome rats, including stroke volume (0.53 ± 0.04 vs. 0.31 ± 0.02, p = 0.0058), ejection fraction (77.67 ± 1.52 vs. 69.16 ± 1.00, p = 0.0002), and fractional shortening (41.02 ± 0.41 vs. 34.36 ± 0.71, p = 0.0027).
Empagliflozin decreased cardiac AngII (1.16 ± 0.06 vs. 1.69 ± 0.02, p < 0.0001) and AT1R (1.27 ± 0.09 vs. 1.97 ± 0.17, p = 0.0068), upregulated AT2R (0.96 ± 0.05 vs. 0.51 ± 0.04, p = 0.0235), and reduced ROS (462.60 ± 64.51 vs. 742.50 ± 26.87, p = 0.0110) and NLRP3 expression (0.93 ± 0.05 vs. 1.47 ± 0.01, p = 0.0013).

Structured PICO

Does empagliflozin improve cardiac function and modulate the local cardiac RAS in a rat model of metabolic syndrome?

P

Population

24 male Wistar rats with high-fat diet-induced metabolic syndrome, treated with empagliflozin for 8 weeks.

I

Intervention

Empagliflozin 10 mg/kg/day via oral gavage for 8 weeks

C

Comparator

Vehicle treatment

O

Outcome

Cardiac function (SV, EF, FS), lipid profile, and local cardiac RAS componentssurrogate

Main Result

Absolute Event Rate: 77.67% vs 69.16%

p-value: p=0.0002

Empagliflozin attenuates cardiac dysfunction in metabolic syndrome by modulating the local cardiac renin-angiotensin system and reducing oxidative stress.

Limitations

Short-term HFD-induced MS model
Blood pressure not assessed
Short treatment duration
Indirect ROS assessment
Only male rats included
Did not allow discrimination between direct cardiac effects and indirect metabolic effects
relatively short-term HFD-induced MS model
blood pressure was not assessed
relatively short treatment duration
ROS levels assessed using indirect ELISA
intracellular Ca2+, cardiac tissue pH, and key RAS components not assessed
did not allow discrimination between direct cardiac effects and indirect metabolic effects
included only male rats
absence of comparison with an NHE1 inhibitor

Implication

Hypothesis-generating in rats; leaves open translation to human metabolic cardiomyopathy and requires clinical trials.

Abstract

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca2+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS.

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Published by Biomedicines · CC BY

Cite This Study

Tarie et al. (2026) studied Metabolic Syndrome (n=24). Empagliflozin vs. Vehicle was evaluated on Ejection fraction (p=0.0002). Empagliflozin significantly improved ejection fraction compared to vehicle in rats with metabolic syndrome (77.67% vs 69.16%, p=0.0002).

synapsesocial.com/papers/6a508cc46eeac72a437a0b61 https://doi.org/10.3390/biomedicines14071533

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Empagliflozin Attenuates Cardiac Dysfunction in Rat Model of Metabolic Syndrome: Evaluating Role of the Cardiac Renin–Angiotensin System

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Figures from the paper

Cite This Study

Empagliflozin Attenuates Cardiac Dysfunction in Rat Model of Metabolic Syndrome: Evaluating Role of the Cardiac Renin–Angiotensin System

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Figures from the paper

Cite This Study

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