Cargando…
The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice
Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven day...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578094/ https://www.ncbi.nlm.nih.gov/pubmed/28777298 http://dx.doi.org/10.3390/ijms18081704 |
_version_ | 1783260467709345792 |
---|---|
author | Nakatsu, Yusuke Kokubo, Hiroki Bumdelger, Batmunkh Yoshizumi, Masao Yamamotoya, Takeshi Matsunaga, Yasuka Ueda, Koji Inoue, Yuki Inoue, Masa-Ki Fujishiro, Midori Kushiyama, Akifumi Ono, Hiraku Sakoda, Hideyuki Asano, Tomoichiro |
author_facet | Nakatsu, Yusuke Kokubo, Hiroki Bumdelger, Batmunkh Yoshizumi, Masao Yamamotoya, Takeshi Matsunaga, Yasuka Ueda, Koji Inoue, Yuki Inoue, Masa-Ki Fujishiro, Midori Kushiyama, Akifumi Ono, Hiraku Sakoda, Hideyuki Asano, Tomoichiro |
author_sort | Nakatsu, Yusuke |
collection | PubMed |
description | Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven days) treatment with the SGLT2 inhibitor luseogliflozin on mRNA levels related to atherosclerosis in the aorta, as well as examining the long-term (six months) effects on atherosclerosis development. Eight-week-old ApoE KO mice were treated with NA/STZ to induce diabetes mellitus, and then divided into two groups, either untreated, or treated with luseogliflozin. Seven days after the initiation of luseogliflozin administration, atherosclerosis-related mRNA levels in the aorta were compared among four groups; i.e., wild type C57/BL6J, native ApoE KO, and NA/STZ-treated ApoE KO mice, with or without luseogliflozin. Short-term luseogliflozin treatment normalized the expression of inflammation-related genes such as F4/80, TNFα, IL-1β, IL-6, ICAM-1, PECAM-1, MMP2 and MMP9 in the NA/STZ-treated ApoE KO mice, which showed marked elevations as compared with untreated ApoE KO mice. In contrast, lipid metabolism-related genes were generally unaffected by luseogliflozin treatment. Furthermore, after six-month treatment with luseogliflozin, in contrast to the severe and widely distributed atherosclerotic changes in the aortas of NA/STZ-treated ApoE KO mice, luseogliflozin treatment markedly attenuated the progression of atherosclerosis, without affecting serum lipid parameters such as high density lipoprotein, low density lipoprotein and triglyceride levels. Given that luseogliflozin normalized the aortic mRNA levels of inflammation-related, but not lipid-related, genes soon after the initiation of treatment, it is not unreasonable to speculate that the anti-atherosclerotic effect of this SGLT2 inhibitor emerges rapidly, possibly via the prevention of inflammation rather than of hyperlipidemia. |
format | Online Article Text |
id | pubmed-5578094 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-55780942017-09-05 The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice Nakatsu, Yusuke Kokubo, Hiroki Bumdelger, Batmunkh Yoshizumi, Masao Yamamotoya, Takeshi Matsunaga, Yasuka Ueda, Koji Inoue, Yuki Inoue, Masa-Ki Fujishiro, Midori Kushiyama, Akifumi Ono, Hiraku Sakoda, Hideyuki Asano, Tomoichiro Int J Mol Sci Article Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven days) treatment with the SGLT2 inhibitor luseogliflozin on mRNA levels related to atherosclerosis in the aorta, as well as examining the long-term (six months) effects on atherosclerosis development. Eight-week-old ApoE KO mice were treated with NA/STZ to induce diabetes mellitus, and then divided into two groups, either untreated, or treated with luseogliflozin. Seven days after the initiation of luseogliflozin administration, atherosclerosis-related mRNA levels in the aorta were compared among four groups; i.e., wild type C57/BL6J, native ApoE KO, and NA/STZ-treated ApoE KO mice, with or without luseogliflozin. Short-term luseogliflozin treatment normalized the expression of inflammation-related genes such as F4/80, TNFα, IL-1β, IL-6, ICAM-1, PECAM-1, MMP2 and MMP9 in the NA/STZ-treated ApoE KO mice, which showed marked elevations as compared with untreated ApoE KO mice. In contrast, lipid metabolism-related genes were generally unaffected by luseogliflozin treatment. Furthermore, after six-month treatment with luseogliflozin, in contrast to the severe and widely distributed atherosclerotic changes in the aortas of NA/STZ-treated ApoE KO mice, luseogliflozin treatment markedly attenuated the progression of atherosclerosis, without affecting serum lipid parameters such as high density lipoprotein, low density lipoprotein and triglyceride levels. Given that luseogliflozin normalized the aortic mRNA levels of inflammation-related, but not lipid-related, genes soon after the initiation of treatment, it is not unreasonable to speculate that the anti-atherosclerotic effect of this SGLT2 inhibitor emerges rapidly, possibly via the prevention of inflammation rather than of hyperlipidemia. MDPI 2017-08-04 /pmc/articles/PMC5578094/ /pubmed/28777298 http://dx.doi.org/10.3390/ijms18081704 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nakatsu, Yusuke Kokubo, Hiroki Bumdelger, Batmunkh Yoshizumi, Masao Yamamotoya, Takeshi Matsunaga, Yasuka Ueda, Koji Inoue, Yuki Inoue, Masa-Ki Fujishiro, Midori Kushiyama, Akifumi Ono, Hiraku Sakoda, Hideyuki Asano, Tomoichiro The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title | The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title_full | The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title_fullStr | The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title_full_unstemmed | The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title_short | The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice |
title_sort | sglt2 inhibitor luseogliflozin rapidly normalizes aortic mrna levels of inflammation-related but not lipid-metabolism-related genes and suppresses atherosclerosis in diabetic apoe ko mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578094/ https://www.ncbi.nlm.nih.gov/pubmed/28777298 http://dx.doi.org/10.3390/ijms18081704 |
work_keys_str_mv | AT nakatsuyusuke thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT kokubohiroki thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT bumdelgerbatmunkh thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT yoshizumimasao thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT yamamotoyatakeshi thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT matsunagayasuka thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT uedakoji thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT inoueyuki thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT inouemasaki thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT fujishiromidori thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT kushiyamaakifumi thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT onohiraku thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT sakodahideyuki thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT asanotomoichiro thesglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT nakatsuyusuke sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT kokubohiroki sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT bumdelgerbatmunkh sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT yoshizumimasao sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT yamamotoyatakeshi sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT matsunagayasuka sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT uedakoji sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT inoueyuki sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT inouemasaki sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT fujishiromidori sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT kushiyamaakifumi sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT onohiraku sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT sakodahideyuki sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice AT asanotomoichiro sglt2inhibitorluseogliflozinrapidlynormalizesaorticmrnalevelsofinflammationrelatedbutnotlipidmetabolismrelatedgenesandsuppressesatherosclerosisindiabeticapoekomice |