Empagliflozin improves primary haemodynamic parameters and attenuates the development of atherosclerosis in high fat diet fed APOE knockout mice

Georgios K Dimitriadis; Narjes Nasiri-Ansari; Georgios Agrogiannis; Ioannis D Kostakis; Manpal S Randeva; Nikolaos Nikiteas; Vanlata H Patel; Gregory Kaltsas; Athanasios G Papavassiliou; Harpal S Randeva; Eva Kassi

doi:10.1016/j.mce.2019.110487

Empagliflozin improves primary haemodynamic parameters and attenuates the development of atherosclerosis in high fat diet fed APOE knockout mice

Mol Cell Endocrinol. 2019 Aug 20:494:110487. doi: 10.1016/j.mce.2019.110487. Epub 2019 Jun 10.

Affiliations

¹ Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK; Division of Endocrinology and Experimental Medicine, Imperial College London, Hammersmith Campus, London, W12 0NN, UK; Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK; Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry, CV1 5FB, UK.
² Department of Biological Chemistry, National and Kapodistrian Univer-sity of Athens Medical School, Athens, Greece.
³ Laboratory of Pathological Anatomy, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁴ Department of Transplantation, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁵ Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
⁶ Laboratory for Experimental Surgery and Surgical Research "N.S. Christeas", Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁷ Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
⁸ 1(st) Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Greece.
⁹ Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK; Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK; Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry, CV1 5FB, UK; Division of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. Electronic address: harpal.randeva@warwick.ac.uk.
¹⁰ Department of Biological Chemistry, National and Kapodistrian Univer-sity of Athens Medical School, Athens, Greece; 1(st) Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: evakassis@gmail.com.

PMID: 31195080
DOI: 10.1016/j.mce.2019.110487

Abstract

The effects of long-term treatment with empagliflozin on biochemical and immunohistochemical markers related to atherosclerosis and atherosclerosis development in the aorta of apolipoprotein E knockout [Apo-E ^(-/-)] mice were evaluated in this study. Empagliflozin-treated mice had lower total cholesterol (P < 0.05), fasting glucose (P < 0.01), heart rate (P < 0.01) and diastolic blood pressure (DBP) (P < 0.05) compared to controls. Histomorphometry revealed reduced atherosclerotic lesion progress approaching statistical significance (P = 0.06) and approximately 50% wider lumen area for the Empagliflozin treated mice group. Although empagliflozin significantly reduced Vcam-1 and Mcp-1 (P < 0.05, P < 0.01, respectively) and marginally induced Timp-1 and Timp-2 mRNA expression (P < 0.08, P = 0.1 respectively), immunohistochemistry revealed a marginal reduction in VCAM-1 and MMP-9 (P = 0.1) without affecting the expression of TIMP-2 and MCP-1 in atherosclerotic lesions. Empagliflozin improves primary haemodynamic parameters and attenuates the progression of atherosclerosis by reducing hyperlipidemia and hyperglycemia, while direct actions in aorta vessel mediated via SGLT-1 are strongly hypothesized.

Keywords: APOE knockout mice; Atherosclerosis; Empagliflozin; Inflammation; SGLT2i.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Atherosclerosis / blood
Atherosclerosis / drug therapy*
Atherosclerosis / pathology
Atherosclerosis / physiopathology*
Benzhydryl Compounds / administration & dosage
Benzhydryl Compounds / pharmacology
Benzhydryl Compounds / therapeutic use*
Blood Glucose / metabolism
Blood Pressure / drug effects
Diastole / drug effects
Diet, High-Fat*
Fasting / blood
Glucosides / administration & dosage
Glucosides / pharmacology
Glucosides / therapeutic use*
Heart Rate / drug effects
Hemodynamics / drug effects*
Lipids / blood
Metalloproteases / metabolism
Mice, Inbred C57BL
Mice, Knockout, ApoE
Plaque, Atherosclerotic / blood
Plaque, Atherosclerotic / drug therapy
Plaque, Atherosclerotic / pathology
Plaque, Atherosclerotic / physiopathology
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Benzhydryl Compounds
Blood Glucose
Glucosides
Lipids
RNA, Messenger
Metalloproteases
empagliflozin