Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat

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Abstract

Background

Empagliflozin (empa), a selective sodium–glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its’ lean control.

Methods

Lean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis.

Results

Empa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats.

Conclusion

Empa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.

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Most cited references 35

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SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart

Chenguang Li, Jie Zhang, Mei Xue … (2019)

Background Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice. Methods Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks. After 8 weeks, heart structure and function were evaluated by echocardiography. Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson’s trichrome stain and Western blot. Results Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis. Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor β/Smad pathway and activation of Nrf2/ARE signaling. Conclusions Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice. Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy.

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Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.

Tohru Minamino, Hideaki Miyauchi, Toshihiko Yoshida … (2002)

The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomere and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implying contributions to atherogenesis. However, whether senescent vascular cells are present in the vasculature and contribute to the pathogenesis of atherosclerosis remains unclear. Senescence-associated beta-galactosidase (beta-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had had ischemic heart diseases. Strong beta-gal stainings were observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. An immunohistochemical analysis using anti-factor VIII antibody demonstrated that beta-gal stained cells are vascular endothelial cells. To determine whether endothelial cell senescence causes endothelial dysfunction, we induced senescence in human aortic endothelial cells (HAECs) by inhibiting telomere function and examined the expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) activity. Senescent HAECs exhibited increased ICAM-1 expression and decreased eNOS activity, both of which are alterations implicated in atherogenesis. In contrast, introduction of telomerase catalytic component significantly extended the life span and inhibited the functional alterations associated with senescence in HAECs. Vascular endothelial cells with senescence-associated phenotypes are present in human atherosclerotic lesions, and endothelial cell senescence induced by telomere shortening may contribute to atherogenesis.

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The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study.

Carlos Lorenzo, Mayor Okoloise, Ken Williams … (2003)

The oral glucose tolerance test identifies high-risk subjects for diabetes, but it is costly and inconvenient. To find better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes. We compared the ability of the National Cholesterol Education Program (NCEP) definition, a modified version of the 1999 World Health Organization (WHO) definition that excludes the 2-h glucose requirement, and impaired glucose tolerance (IGT) to predict incident type 2 diabetes. In the San Antonio Heart Study, 1734 participants completed a 7- to 8-year follow-up examination. IGT and the NCEP definition had higher sensitivity than the modified WHO definition (51.9, 52.8, and 42.8%, respectively). IGT had a higher positive predictive value than the NCEP and modified WHO definitions (43.0, 30.8, and 30.4%, respectively). The combination of the IGT and NCEP definitions increased the sensitivity to 70.8% with an acceptable positive predictive value of 29.7%. Risk for incidence of type 2 diabetes using the NCEP definition was independent of other risk factors, including IGT and fasting insulin (odds ratio 3.30, 95% CI 2.27-4.80). The NCEP definition performed better with fasting glucose >or=5.4 mmol/l (sensitivity 62.0% and positive predictive value 30.9%). The metabolic syndrome predicts diabetes independently of other factors. However, the NCEP definition performs better than the modified 1999 WHO definition. Lowering the fasting glucose cutoff to 5.4 mmol/l improves the prediction of diabetes by the metabolic syndrome.

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Author and article information

Contributors

Valérie B. Schini-Kerth: valerie.schini-kerth@unistra.fr

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 18 February 2020

Publication date PMC-release: 18 February 2020

Publication date Collection: 2020

Volume: 19

Electronic Location Identifier: 19

Affiliations

[1 ]INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France

[2 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Hôpitaux Universitaires de Strasbourg, Service des Maladies Vasculaires - Hypertension Artérielle, ; Strasbourg, France

[3 ]GRID grid.463906.e, ISNI 0000 0004 0368 2086, UMR CNRS 7021 Laboratoire de Bioimagerie et Pathologies, ; Strasbourg, France

[4 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Hôpitaux Universitaires de Strasbourg, Service de Cardiologie, ; Strasbourg, France

[5 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Laboratory of Biochemistry and Molecular Biology, , Hôpitaux Universitaires de Strasbourg, ; Strasbourg, France

[6 ]GRID grid.420061.1, ISNI 0000 0001 2171 7500, Boehringer Ingelheim Pharma GmbH & Co. KG, ; Biberach, Germany

Article

Publisher ID: 997

DOI: 10.1186/s12933-020-00997-7

PMC ID: 7026972

PubMed ID: 32070346

SO-VID: 35c0ccb7-9dc7-4768-8ac1-60685cdc4ac4

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 31 October 2019

Date accepted : 6 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100008349, Boehringer Ingelheim;

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: empagliflozin,sglt2,endothelial function,heart function,heart structure,senescence,zsf1,metabolic syndrome

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: empagliflozin, sglt2, endothelial function, heart function, heart structure, senescence, zsf1, metabolic syndrome