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Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice
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Nasiri-Ansari, Narjes, Dimitriadis, Georgios K., Agrogiannis, Georgios, Perrea, Despoina, Kostakis, Ioannis D., Kaltsas, Gregory, Papavassiliou, Athanasios G., Randeva, Harpal S. and Kassi, Eva (2018) Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovascular Diabetology, 17 . 106. doi:10.1186/s12933-018-0749-1
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Official URL: https://doi.org/10.1186/s12933-018-0749-1
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.
| Item Type: | Journal Article | ||||||
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| Subjects: | R Medicine > RC Internal medicine | ||||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Atherosclerosis, Inflammation, Non-insulin-dependent diabetes -- Treatment | ||||||
| Journal or Publication Title: | Cardiovascular Diabetology | ||||||
| Publisher: | Biomed central | ||||||
| ISSN: | 1475-2840 | ||||||
| Official Date: | 26 July 2018 | ||||||
| Dates: |
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| Date of first compliant deposit: | 1 August 2018 | ||||||
| Volume: | 17 | ||||||
| Article Number: | 106 | ||||||
| DOI: | 10.1186/s12933-018-0749-1 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access |
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