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.
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.
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DOI：
10.3390/ijms18081704
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发表时间：
2017-08-04
影响因子：
5.6
通讯作者：
Asano T
中科院分区：
文献类型：
--
作者：
Nakatsu Y;Kokubo H;Bumdelger B;Yoshizumi M;Yamamotoya T;Matsunaga Y;Ueda K;Inoue Y;Inoue MK;Fujishiro M;Kushiyama A;Ono H;Sakoda H;Asano T
最近的临床研究显示，使用钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂治疗糖尿病患者可降低心血管事件的发生率。使用烟酰胺和链脲佐菌素（NA/STZ）处理的ApoE KO小鼠，我们研究了SGLT 2抑制剂luseoglivin短期（7天）处理对主动脉粥样硬化相关mRNA水平的影响，以及对动脉粥样硬化发展的长期（6个月）影响。用NA/STZ处理八周龄ApoE KO小鼠以诱导糖尿病，然后分成两组，未处理或用鲁司格列汀处理。在开始鲁塞格列汀给药后7天，比较四组之间主动脉中动脉粥样硬化相关mRNA水平;即，野生型C57/BL 6 J、天然ApoE KO和NA/STZ处理的ApoE KO小鼠，含或不含鲁司格列汀。短期鲁司格列净治疗使NA/STZ治疗的ApoE KO小鼠中炎症相关基因（如F4/80、TNFα、IL-1β、IL-6、ICAM-1、PECAM-1、MMP 2和MMP 9）的表达正常化，与未治疗的ApoE KO小鼠相比，其显示出显著升高。相反，脂质代谢相关基因通常不受鲁索格列汀治疗的影响。此外，在用鲁塞格列净治疗6个月后，与NA/STZ治疗的ApoE KO小鼠的动脉粥样硬化中严重且广泛分布的动脉粥样硬化变化相反，鲁塞格列净治疗显著减弱动脉粥样硬化的进展，而不影响血清脂质参数，如高密度脂蛋白、低密度脂蛋白和甘油三酯水平。鉴于鲁格列净在治疗开始后不久就使炎症相关基因（而非脂质相关基因）的主动脉mRNA水平正常化，因此推测这种SGLT 2抑制剂的抗动脉粥样硬化作用迅速出现并不合理，可能是通过预防炎症而不是高脂血症。
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.
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影响因子：
10.8
作者：
Merhi-Soussi, F;Kwak, BR;Gabay, C
通讯作者：
Gabay, C
影响因子：
4.6
作者：
Leng W;Ouyang X;Lei X;Wu M;Chen L;Wu Q;Deng W;Liang Z
通讯作者：
Liang Z
DOI：
10.1056/nejmoa1603827
发表时间：
2016-07-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Marso SP;Daniels GH;Brown-Frandsen K;Kristensen P;Mann JF;Nauck MA;Nissen SE;Pocock S;Poulter NR;Ravn LS;Steinberg WM;Stockner M;Zinman B;Bergenstal RM;Buse JB;LEADER Steering Committee;LEADER Trial Investigators
通讯作者：
LEADER Trial Investigators
影响因子：
3.5
作者：
Marchesini, G;Forlani, G;Melchionda, N
通讯作者：
Melchionda, N
影响因子：
3.7
作者：
Lee G;Oh SW;Hwang SS;Yoon JW;Kang S;Joh HK;Kwon H;Kim J;Park D
通讯作者：
Park D