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Cardiovasc Diabetol. 2018 Jul 26;17(1):106. doi: 10.1186/s12933-018-0749-1.

Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice.

Author information

1
Department of Biological Chemistry, National and Kapodistrian University of Athens Medical School, Athens, Greece.
2
Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
3
Division of Endocrinology and Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
4
Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
5
Laboratory of Pathological Anatomy, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
6
Laboratory for Experimental Surgery and Surgical Research "N.S. Christeas", Medical School, National and Kapodistrian University of Athens, Athens, Greece.
7
Second Department of Propedeutic Surgery, National and Kapodistrian University of Athens, Medical School, 'Laiko' General Hospital, Athens, Greece.
8
Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK. harpal.randeva@warwick.ac.uk.
9
Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK. harpal.randeva@warwick.ac.uk.
10
Division of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. harpal.randeva@warwick.ac.uk.
11
Department of Biological Chemistry, National and Kapodistrian University of Athens Medical School, Athens, Greece. ekassi@med.uoa.gr.
12
First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece. ekassi@med.uoa.gr.

Abstract

BACKGROUND:

Sodium glucose co-transporter2 inhibitors reduce the incidence of cardiovascular events in patients with type 2 diabetes mellitus based on the results of recent cardiovascular outcome studies. Herein, we investigated the effects of long-term treatment with canagliflozin on biochemical and immunohistochemical markers related to atherosclerosis and atherosclerosis development in the aorta of apolipoprotein E knockout (Apo-E(-/-)) mice.

METHODS:

At the age of 5 weeks, mice were switched from normal to a high-fat diet. After 5 weeks, Apo-E(-/-) mice were divided into control-group (6 mice) treated with 0.5% hydroxypropyl methylcellulose and Cana-group (7 mice) treated with canagliflozin (10 mg/kg per day) per os. After 5 weeks of intervention, animals were sacrificed, and heart and aorta were removed. Sections stained with hematoxylin-eosin (H&E) were used for histomorphometry whereas Masson's stained tissues were used to quantify the collagen content. Immunohistochemistry to assess MCP-1, CD68, a-smooth muscle actin, MMP-2, MMP-9, TIMP-1 and TIMP-2 expression was carried out and q-PCR experiments were performed to quantify mRNA expression.

RESULTS:

Canagliflozin-group mice had lower total-cholesterol, triglycerides and glucose levels (P < 0.01), while heart rate was significantly lower (P < 0.05). Histomorphometry revealed that one in seven Cana-group mice versus four in six control mice developed atheromatosis, while aortic root plaque was significantly less, and collagen was 1.6 times more intense in canagliflozin-group suggesting increased plaque stability. Immunohistochemistry revealed that MCP-1 was significantly less expressed (P < 0.05) in the aortic root of canagliflozin-group while reduced expression of a-actin and CD68 was not reaching significance (P = 0.15). VCAM-1 and MCP-1 mRNA levels were lower (P = 0.02 and P = 0.07, respectively), while TIMP-1/MMP-2 ratio expression was higher in canagliflozin-group approaching statistical significance (P = 0.07).

CONCLUSIONS:

Canagliflozin attenuates the progression of atherosclerosis, reducing (1) hyperlipidemia and hyperglycemia, and (2) inflammatory process, by lowering the expression of inflammatory molecules such as MCP-1 and VCAM-1. Moreover, canagliflozin was found to increase the atherosclerotic plaque stability via increasing TIMP-1/MMP-2 ratio expression.

KEYWORDS:

APOE knockout mice; Atherosclerosis; Canagliflozin; Inflammation; SGLT2i

PMID:
30049285
PMCID:
PMC6063004
DOI:
10.1186/s12933-018-0749-1
[Indexed for MEDLINE]
Free PMC Article

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