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Cardiovascular inflammation is reduced with methotrexate in diabetes

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Abstract

Diabetes increases the risk of vascular events and mortality. While earlier type 2 diabetes trials demonstrated that intensive glucose lowering reduces microvascular complications, it is only recently that treatment with some of the newer antihyperglycemic agents has been associated with macrovascular benefits. We report herein that db/db mice concomitantly fed the Western diet and treated with the anti-inflammatory agent methotrexate display a less aggressive inflammatory (lower serum IL-1β, IL-6, SDF-1, and TNFα levels; higher circulating adiponectin, IL-12p70 and IL-10 concentrations; lower aortic VCAM-1 levels) profile than their saline-treated counterpart. Furthermore, acetylcholine-elicited endothelium-dependent vasodilatation was significantly greater in thoracic aortic segments from the former group. Collectively, the data lend support to the notion that alterations in the inflammatory system may be involved in the macrovascular benefits observed in type 2 diabetes trials and provide credence for the development of anti-inflammatory tools to lower CV risk and CV events in diabetes.

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Abbreviations

A1C:

Glycated hemoglobin

CBC:

Complete blood count

CEU:

Contrast-enhanced ultrasound

CHD:

Coronary heart disease

CIRT:

Cardiovascular inflammation reduction trial

CV:

Cardiovascular

db/db:

Cg-Dock7 m+/+ Lepr db/J

db/m:

Dock7 m+/+ Lepr db

HDL:

High-density lipoprotein

IL:

Interleukin

LDL:

Low-density lipoprotein

MTX:

Methotrexate

PI:

Pulsing interval

SDF:

Stromal cell-derived factor

TNF:

Tumor necrosis factor

VCAM:

Vascular cell adhesion molecule

VLDL:

Very low-density lipoprotein

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Acknowledgements

This work was in part supported by funding awarded to S. Verma from the Canada Research Chairs Program, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Canada.

Authors contribution

AQ and SV conceived and developed the study design. AQ, YP, KKS, JP, and HLP collected and analyzed the data. AQ, HT, and HLP wrote the first draft. AQ, HT, HLP, and SV critically revised the manuscript. All authors reviewed the manuscript and approved submission of the final version.

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Authors and Affiliations

  1. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 8th Floor Bond Wing, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Adrian Quan, Yi Pan, Krishna K. Singh, John Polemidiotis, Hwee Teoh & Subodh Verma

  2. Division of Vascular Surgery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada

    Krishna K. Singh

  3. Division of Endocrinology & Metabolism, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada

    Hwee Teoh

  4. Division of Cardiology, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada

    Howard Leong-Poi

  5. Department of Surgery, University of Toronto, Toronto, Canada

    Krishna K. Singh & Subodh Verma

  6. Department of Medicine, University of Toronto, Toronto, Canada

    Howard Leong-Poi

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  1. Adrian Quan
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Correspondence to Subodh Verma.

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Quan, A., Pan, Y., Singh, K.K. et al. Cardiovascular inflammation is reduced with methotrexate in diabetes. Mol Cell Biochem 432, 159–167 (2017). https://doi.org/10.1007/s11010-017-3006-0

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