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Empagliflozin restores the integrity of the endothelial glycocalyx in vitro

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Abstract

The antihyperglycemic agent empagliflozin not only improves glycemic control but has also been associated with clinically meaningful reductions in cardiovascular events. Studies have shown that empagliflozin significantly reduces cardiovascular death and heart failure-associated hospitalizations. Given that endothelial dysfunction is closely linked with the pathogenesis of atherosclerotic cardiovascular disease, we hypothesized that the cardiovascular benefits observed with empagliflozin may be a result of its positive impact on the health of the endothelial glycocalyx (GCX), a critical component for the endothelium homeostasis. Human abdominal aortic endothelial cells (HAAECs) were either statically cultured or subjected to a steady wall shear stress of 10 dyne/cm2. Empagliflozin (50 µM, 24 h) restored heparinase III-mediated GCX disruption and the normal mechanotransduction responses in GCX-compromised HAAECs while reducing the attachment of all-trans retinoic acid-transformed NB4 cells to HAAECs. The current body of work suggests that the cardioprotective properties previously reported for empagliflozin may in part be due to the ability of empagliflozin to preserve and restore the structural integrity of the GCX, which in turn helps to maintain vascular health by promoting an anti-inflammatory endothelium, in the presence of a pro-inflammatory environment. Further studies are needed to fully understand the mechanisms underlying the cardiovascular benefits of empagliflozin.

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Abbreviations

ATRA:

All-trans retinoic acid

CVD:

Cardiovascular disease

ICAM-1:

Intercellular adhesion molecule 1

SGLT2:

Sodium-glucose co-transporter-2

SI:

Shape index

T2DM:

Type 2 diabetes mellitus

TNFα:

Tumor necrosis factor α

VCAM-1:

Vascular cell adhesion molecule 1

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Funding

This research was supported by NSERC 261938-13 RL. SV was the Canada Research Chair in Atherosclerosis at the University of Toronto.

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Authors and Affiliations

  1. Department of Chemical Engineering, McGill University, 3610 University Street, Montréal, QC, H3A 2B2, Canada

    Scott Cooper, Marc Antoine Campeau & Richard L. Leask

  2. Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada

    Hwee Teoh

  3. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada

    Hwee Teoh & Subodh Verma

  4. Departments of Surgery, and Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Subodh Verma

  5. Montreal Heart Institute, Montréal, QC, Canada

    Richard L. Leask

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  1. Scott Cooper
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Contributions

SV and RLL conceived the study. SC and RLL designed the study. MAC and SC acquired the data and SC analyzed the data. SC, HT, SV and RLL interpreted the analyses. SC drafted the manuscript. All authors participated in revising the manuscript and approved the final version to be published. RLL is the guarantor of this work.

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Correspondence to Richard L. Leask.

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Conflict of interest

Hwee Teoh reports receiving honorarium from Boehringer Ingelheim. Subodh Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk and Sanofi. He is also the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization.

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Cooper, S., Teoh, H., Campeau, M.A. et al. Empagliflozin restores the integrity of the endothelial glycocalyx in vitro. Mol Cell Biochem 459, 121–130 (2019). https://doi.org/10.1007/s11010-019-03555-2

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