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Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

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Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5–20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.

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Abbreviations

ACh:

Acetylcholine

ADA:

Adenine deaminase

AMPK:

AMP-activated protein kinase

aPTT:

Activated partial thromboplastin time

CCL-2:

See MCP-1

DHE:

Dihydroethidine

DPP-4:

Dipeptidyl peptidase-4

ECL:

Enhanced chemiluminescence

ecSOD:

Extracellular superoxide dismutase

eNOS:

Endothelial •NO synthase (type 3)

GLP-1:

Glucagon-like peptide-1

ICAM-1:

Intercellular adhesion molecule-1

IL-6:

Interleukin-6

iNOS:

Inducible •NO synthase (type 2)

L-012:

8-Amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt

MCP-1:

Monocyte chemoattractant protein-1

Nox:

Catalytic subunit of NADPH oxidase

NIBP:

Non-invasive blood pressure

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-α

VCAM-1:

Vascular adhesion molecule-1

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Acknowledgments

We are indebted to Angelica Karpi, Jörg Schreiner, Jessica Rudolph, Bettina Mros and Evelyn Montermann for expert technical assistance. This paper contains results that are part of the doctoral thesis of Michael Mader. The present work was supported by vascular biology research grants from Boehringer Ingelheim Pharma GmbH & Co. KG (A.D. and T.M.). Sebastian Steven holds a Virchow-Fellowship from the Center of Thrombosis and Hemostasis (Mainz, Germany) funded by the Federal Ministry of Education and Research (BMBF 01EO1003). Yuliya Miked holds a stipend from the International PhD Programme on the “Dynamics of Gene Regulation, Epigenetics and DNA Damage Response” from the Institute of Molecular Biology gGmbH, (Mainz, Germany) funded by the Boehringer Ingelheim Foundation.

Conflict of interest

A.D. and T.M. received research grant support from Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. T.K. is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. All other authors have no competing financial interests.

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Author notes

    Authors and Affiliations

    1. Department of Cardiology, 2nd Medical Clinic, Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Sebastian Steven, Michael Hausding, Swenja Kröller-Schön, Michael Mader, Yuliya Mikhed, Paul Stamm, Elena Zinßius, Amanda Pfeffer, Philipp Welschof, Saule Agdauletova, Matthias Oelze, Eberhard Schulz, Thomas Münzel & Andreas Daiber

    2. Center of Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Sebastian Steven

    3. Department of Dermatology, Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Stephan Sudowe

    4. Department of Pharmacology, Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Huige Li

    5. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

      Thomas Klein

    6. II. Medizinische Klinik und Poliklinik, Labor für Molekulare Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Geb. 605, Raum 3.262, Langenbeckstr. 1, 55131, Mainz, Germany

      Andreas Daiber

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    Correspondence to Andreas Daiber.

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    S. Steven and M. Hausding contributed equally to this study and should therefore both be considered as first author.

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    Steven, S., Hausding, M., Kröller-Schön, S. et al. Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia. Basic Res Cardiol 110, 6 (2015). https://doi.org/10.1007/s00395-015-0465-x

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    • DOI: https://doi.org/10.1007/s00395-015-0465-x

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