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 the in vitro and in vivo effects 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.

胰岛素敏感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，并诱导脂肪组织（脂肪）产生血管保护蛋白脂联素。由于内膜增生发展引起的狭窄通常发生在放置用于血液透析的动静脉合成移植物之后。进行这项工作是为了表征在脂肪中ROS或PGZ掺入的体外和体内作用，并确定在血液透析动静脉移植物狭窄的猪模型中，脂肪/ PGZ贮库是否可以减少血管增生的发展。

将粉状的ROS或PGZ（6-6000μM）与脂肪外植体混合并进行培养。通过HPLC / MS / MS定量测定从脂肪中释放的药物，并通过ELISA测定培养基中脂联素和单核细胞趋化蛋白-1（MCP-1）的水平。用DNA结合测定法测量了用ROS或PGZ脂肪培养的条件培养基对i）血小板衍生的生长因子-BB（PDGF-BB）刺激的人静脉平滑肌细胞（SMC）增殖的影响， ii）通过ELISA评估脂多糖（LPS）诱导的人单核细胞释放肿瘤坏死因子-α（TNFα）。在猪模型中，通过HPLC / MS / MS评估从血管周围移植到颈静脉的脂肪储库中PGZ的药代动力学，并通过MRI监测脂肪储库的保留。

ROS和PGZ均显着诱导脂联素的释放并抑制MCP-1从脂肪中的释放。在单独受脂肪或脂肪与任一种药物共同作用的培养基中，LPS刺激单核细胞产生的TNF抑制了50-70％。在由脂肪/ ROS培养物调节的培养基存在下，SMC的增殖受到抑制。放置在血管瘤周围颈外静脉的脂肪外植体得以保留，这在放置后1周通过MRI得以确认。PGZ在脂肪储库，颈外静脉壁和邻近组织中以临床相关水平检测到，而血浆中水平低于检测到。与单独暴露于脂肪的静脉相比，暴露于掺有PGZ的脂肪的颈外静脉具有增加的脂联素表达。然而，