Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice
Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice
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DOI：
10.1186/s12933-019-0886-1
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发表时间：
2019-06-24
影响因子：
9.3
通讯作者：
Kitamura, Kenichiro
中科院分区：
文献类型：
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作者：
Mori, Kentaro;Tsuchiya, Kyoichiro;Kitamura, Kenichiro
背景血管周围脂肪组织(PVAT)在心血管疾病的发病机制中起着重要作用。目前尚不清楚在2型糖尿病(T2 DM)患者中抑制钠葡萄糖共转运体2(SGLT2)是否会影响PVAT的特征，以及SGLT2抑制剂引起的脂肪组织改变，特别是脂肪组织来源的分泌因子的变化是否会影响血管病理生理。方法用西式饮食(WD)喂养野生型小鼠，用或不加SGLT2抑制剂伊普洛齐(IPRA)治疗10周。将WEHI274.1和原代血管平滑肌细胞与喂饲WD的IPRA或赋形剂处理的小鼠的附睾脂肪组织条件培养液(CM)或腹壁PVAT孵育。将IPRA或赋形剂治疗组小鼠的EPI植入apoE缺陷小鼠的股动脉袖套处。结果Ipra增加了腹壁PVAT中脂肪细胞的体积，并降低了促炎和纤维化相关基因的表达。IPRA还可抑制WD诱导的腹壁PVAT中巨噬细胞的聚集、纤维化和脂肪细胞死亡。IPRA处理组小鼠腹部PVAT的CM中瘦素浓度显著低于赋形剂处理组小鼠。在体外，赋形剂处理组小鼠的WEHI-274.1和原代血管平滑肌细胞的迁移能力明显高于异丙肾上腺素处理组的小鼠。与载脂蛋白E缺陷小鼠相比，IPRA处理的小鼠血管周围植入EPI可减轻袖套诱导的新生内膜增生和血管重塑。结论IPRA诱导的腹壁PVAT的改变将有助于更好地了解SGLT2抑制剂预防T2 DM心血管并发症的机制，并针对PVAT开发新的治疗策略。
BackgroundPerivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. It is unclear whether inhibition of sodium glucose cotransporter 2 (SGLT2) in subjects with type 2 diabetes (T2DM) could affect PVAT characters, and whether the SGLT2 inhibitors-induced changes of adipose tissue, especially the alternation of adipose tissue-derived secretory factors, affect vascular pathophysiology.MethodsWestern-type diet (WD) fed wild-type mice were treated with or without an SGLT2 inhibitor ipragliflozin (Ipra) for 10weeks. WEHI 274.1 and primary vascular smooth muscle cells were incubated with conditioned media (CM) of epididymal adipose tissue (Epi) or abdominal PVAT of Ipra- or vehicle-treated mice fed a WD. Epi of Ipra- or vehicle-treated mice fed a WD was implanted onto cuff-placed femoral arteries of apoE-deficient mice.ResultsIpra increased adipocyte size associated with decreased expression of pro-inflammatory and fibrosis-related genes in abdominal PVAT of WD-fed mice. Ipra also suppressed WD-induced macrophages accumulation, fibrosis, and adipocyte death in abdominal PVAT. In CM of abdominal PVAT from Ipra-treated mice, concentration of leptin was significantly lower than that from vehicle-treated mice. In vitro, migration of WEHI 274.1 and primary vascular smooth muscle cells were more enhanced by CM of Epi or abdominal PVAT from vehicle-treated mice than that from Ipra-treated mice. Perivascular implantation of Epi from Ipra-treated mice to apolipoprotein E-deficient mice attenuated cuff-induced neointimal hyperplasia and vascular remodeling compared to that from vehicle-treated mice.ConclusionsThe Ipra-induced changes of abdominal PVAT will lead to a better understanding of unveiled mechanisms by which SGLT2 inhibitors prevent cardiovascular complications in T2DM, and the development of new therapeutic strategies targeting PVAT.