SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis.
SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis.
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SMTP-44 D通过抑制AGEs-β轴部分抑制载脂蛋白-E β小鼠动脉粥样硬化斑块形成
DOI：
10.3390/ijms24076505
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发表时间：
2023-03-30
影响因子：
5.6
通讯作者：
Yamagishi, Sho-ichi
中科院分区：
文献类型：
--
作者：
Terasaki, Michishige;Shibata, Keita;Mori, Yusaku;Saito, Tomomi;Matsui, Takanori;Ohara, Makoto;Fukui, Tomoyasu;Hasumi, Keiji;Higashimoto, Yuichiro;Nobe, Koji;Yamagishi, Sho-ichi
SMTP-44 D具有抗氧化和抗炎作用，包括降低实验性糖尿病神经病变中晚期糖基化终产物受体（RECEPTOR for Advanced Glycation End Products，RECEPTOR）的表达。尽管SMTP-44 D及其配体和晚期糖基化终产物（AGEs）的激活在动脉粥样硬化性心血管疾病（糖尿病患者死亡的主要原因）中起着至关重要的作用，但目前尚不清楚SMTP-44 D是否可以通过抑制AGEs-β轴来抑制实验性动脉粥样硬化。在这项研究中，我们研究了SMTP-44 D对载脂蛋白E缺失（Apoe−/−）小鼠动脉粥样硬化斑块形成和AGEs表达的影响。我们在此进一步研究了SMTP-44 D是否以及如何抑制从Apoe−/−小鼠离体分离的巨噬细胞的泡沫细胞形成。虽然给予Apoe−/−小鼠SMTP-44 D不会影响临床或生化参数，但它显著降低了动脉粥样硬化病变的表面积，并减少了动脉粥样硬化斑块的大小、巨噬细胞浸润和主动脉根部AGEs的积累。SMTP-44 D结合到固定化的AGEs上，随后在体外减弱AGEs与AGEs的相互作用。此外，通过Dil-氧化低密度脂蛋白（ox-LDL）摄取评估的泡沫细胞形成，以及从SMTP-44 D处理的Apoe−/−小鼠分离的巨噬细胞中的CD 36、细胞周期蛋白依赖性激酶5（Cdk 5）和CD 36的基因表达与盐水处理的小鼠相比显著降低。CD 36和CDK 5基因表达水平高度相关，CDK 5基因表达水平与CD 36基因表达水平呈正相关。本研究表明，SMTP-44 D可能通过抑制Cdk 5-CD 36通路，部分阻断AGEs-β诱导的ox-LDL进入巨噬细胞，从而抑制Apoe−/−小鼠动脉粥样硬化斑块的形成。
SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs–RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe−/−) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe−/− mice ex vivo. Although administration of SMTP-44D to Apoe−/− mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe−/− mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe−/− mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.
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影响因子：
2
作者：
Hashimoto, Terumasa;Shibata, Keita;Nobe, Koji
通讯作者：
Nobe, Koji
影响因子：
5.6
作者：
Hasumi K;Suzuki E
通讯作者：
Suzuki E
影响因子：
3.1
作者：
Fukami, Kei;Yamagishi, Sho-ichi;Okuda, Seiya
通讯作者：
Okuda, Seiya
影响因子：
4.6
作者：
Bijnen M;Beelen N;Wetzels S;Gaar JV;Vroomen M;Wijnands E;Scheijen JL;van de Waarenburg MPH;Gijbels MJ;Cleutjens JP;Biessen EAL;Stehouwer CDA;Schalkwijk CG;Wouters K
通讯作者：
Wouters K
影响因子：
8.2
作者：
Nagashima, M.;Watanabe, T.;Terasaki, M.;Tomoyasu, M.;Nohtomi, K.;Kim-Kaneyama, J.;Miyazaki, A.;Hirano, T.
通讯作者：
Hirano, T.