Autologous fat transplants to deliver glitazone and adiponectin for vasculoprotection.
Autologous fat transplants to deliver glitazone and adiponectin for vasculoprotection.
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自体脂肪移植可提供格列酮和脂联素以保护血管。
DOI：
10.1016/j.jconrel.2017.08.036
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Terry,ChristiM
中科院分区：
文献类型：
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作者：
Sanders,WilliamG;Li,Huan;Zhuplatov,Ilya;He,Yuxia;Kim,Seong-Eun;Cheung,AlfredK;Agarwal,Jayant;Terry,ChristiM
胰岛素增敏性格列酮类药物罗格列酮(ROS)和吡格列酮(PGZ)均具有抗增殖和抗炎作用，并能诱导脂肪组织产生血管保护蛋白脂联素。动静脉动静脉复合移植物用于血液透析后，常因血管内膜增生性狭窄发生。本研究旨在研究ROS或PGZ在脂肪中掺入的体外和活体效应，并确定脂肪/PGZ在猪动静脉移植物狭窄血液透析模型中是否能减少血管增生的发展。将ROS或PGZ(6-6000μM)粉末与脂肪外植体混合培养。用高效液-质联用法定量脂肪释放药物，用酶联免疫吸附试验检测培养上清中脂联素和单核细胞趋化蛋白-1(MCP-1)水平。用DNA结合法检测ROS或PGZ对血小板衍生生长因子-BB(PDGFR-BB)刺激的人静脉平滑肌细胞增殖的影响；用ELISA法检测脂多糖诱导人单核细胞释放肿瘤坏死因子-α(α)的作用。在猪模型中，用高效液相色谱/质谱仪/质谱仪分析了PGZ从脂肪库移植到血管周围到颈静脉的药代动力学，并用MRI监测了脂肪库的滞留情况。在猪颈总动脉和同侧颈静脉之间建立的人工血管移植模型上，观察了PGZ/脂肪库对血管增殖发育的影响。ROS和PGZ均能显著诱导脂联素的释放，并抑制MCP-1的释放。单核细胞经内毒素刺激后，单核细胞产生的肿瘤坏死因子在脂肪单独或脂肪加任何一种药物的培养液中均被抑制50-70%。在含FAT/ROS条件培养液中，SMC的增殖受到抑制。放置在颈外静脉血管周围的脂肪外植体被保留，放置一周后的MRI证实。在脂肪库、颈外静脉壁和邻近组织中检测到临床相关水平的PGZ，而血浆中的水平低于检测水平。与单独暴露于脂肪的静脉相比，颈外静脉暴露于脂肪联合PGZ后脂联素的表达增加。然而，与不进行任何处理相比，使用FAT/PGZ代谢物处理的动静脉合成移植物内的增生发展没有变化。
The insulin sensitizing glitazone drugs, rosiglitazone (ROS) and pioglitazone (PGZ) both have anti-proliferative and anti-inflammatory effects and induce adipose tissue (fat) to produce the vaso-protective protein adiponectin. Stenosis due to intimal hyperplasia development often occurs after placement of arteriovenous synthetic grafts used for hemodialysis. This work was performed to characterize thein vitroandin vivoeffects of ROS or PGZ incorporation in fat and to determine if fat/PGZ depots could decrease vascular hyperplasia development in a porcine model of hemodialysis arteriovenous graft stenosis.Powdered ROS or PGZ (6–6000 μM) was mixed with fat explants and cultured. Drug release from fat was quantified by HPLC/MS/MS, and adiponectin and monocyte chemotactic protein-1 (MCP-1) levels in culture media were measured by ELISA. The effect of conditioned media from the culture of fat with ROS or PGZ on i) platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation of human venous smooth muscle cells (SMC) was measured by a DNA-binding assay, and ii) lipopolysaccharide (LPS)-induced human monocyte release of tumor necrosis factor-alpha (TNFα) was assessed by ELISA. In a porcine model, pharmacokinetics of PGZ from fat depots transplanted perivascular to jugular vein were assessed by HPLC/MS/MS, and retention of the fat depot was monitored by MRI. A porcine model of synthetic graft placed between carotid artery and ipsilateral jugular vein was used to assess effects of PGZ/fat depots on vascular hyperplasia development.Both ROS and PGZ significantly induced the release of adiponectin and inhibited release of MCP-1 from the fat. TNF production from monocytes stimulated with LPS was inhibited 50–70% in the presence of media conditioned by fat alone or fat and either drug. The proliferation of SMC was inhibited in the presence of media conditioned by fat/ROS cultures. Fat explants placed perivascular to the external jugular vein were retained, as confirmed by MRI at one week after placement. PGZ was detected in the fat depot, in the external jugular vein wall and in adjacent tissue at clinically relevant levels, whereas levels in plasma were below detection. External jugular vein exposed to fat incorporated with PGZ had increased adiponectin expression compared to vein exposed to fat alone. However, the development of hyperplasia within the arteriovenous synthetic grafts was unchanged by treatment with fat/PGZ depots compared to no treatment.