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.

Yusuke Nakatsu,Masa-Ki Inoue,Tomoichiro Asano,Midori Fujishiro,Koji Ueda,Hiraku Ono,Masao Yoshizumi,Takeshi Yamamotoya,Hiroki Kokubo,Yuki Inoue,Hideyuki Sakoda,Yasuka Matsunaga,Akifumi Kushiyama,Batmunkh Bumdelger

doi:10.3390/ijms18081704

Abstract

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.

Highlights

It is well established that the development of cardiovascular (CV) disease or atherosclerosis is accelerated in patients with a clustering of risk factors [1,2]
From the standpoint of pathogenesis, inflammation is profoundly involved in the development of atherosclerosis
At the six-month endpoint after nicotinamide and streptozotocin (NA/STZ) followed by luseogliflozin treatment, a marked difference in the degree of atherosclerosis was observed. These results clearly indicate that hyperglycemia alone, not necessarily accompanied by insulin resistance, is sufficient for atherosclerosis acceleration in the presence of hyperlipidemia

Summary

Introduction

It is well established that the development of cardiovascular (CV) disease or atherosclerosis is accelerated in patients with a clustering of risk factors [1,2]. This clustering, known as metabolic syndrome, includes the established risk factors of visceral obesity, hyperlipidemia, hyperglycemia, hyperinsulinemia with insulin resistance, hyperuricemia and hypertension [3,4]. Increases in inflammatory cytokines are well known to be closely linked with the exacerbation of atherosclerosis. Increased expression of inflammatory cytokines, which are secreted by macrophages, leads to the destabilization of plaque in the aorta [5]

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Results

Conclusion