Autologous fat transplants to deliver glitazone and adiponectin for vasculoprotection

Abstract

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 (PDGG-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.

The Effects of Pro-Inflammatory and Anti-Inflammatory Agents for the Suppression of Intimal Hyperplasia: An Evidence-Based Review

“…Inflammation within the vascular wall is a hurdle, and manipulating the inflammatory cytokines and chemokines is possibly the key piece in solving the puzzle. Other than that, research related to inhibition of intimal hyperplasia has also been extensively done using various approaches, which utilized gene therapy and vector-mediated gene delivery [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ], anti-inflammatory and anti-proliferative drugs [ 57 ], compounds with anti-inflammatory actions such as plants [ 55 , 65 ], herbal medications [ 50 ], marine sources [ 52 ] and polyunsaturated fatty acids [ 56 ].…”

“…In a previous study by Sanders and co-workers [ 57 ], the utilization of anti-inflammatory and anti-proliferative agents, mainly both rosiglitazone (ROS) and pioglitazone (PGZ), has a significant effect in decreasing inflammation and cell proliferation and being able to supply a longer drug delivery to the adjoining tissue. The glitazone drugs, primarily ROS and PGZ, possess anti-inflammatory effects, which were used to induce adipose tissue to produce the vascular protective protein such as adiponectin.…”

“…They also evaluated the feasibility of fat integrated with PGZ storage in decreasing intimal hyperplasia development in animal model. This novel approach of utilizing anti-inflammatory agents could possibly be considered as an alternative therapy to suppress arterial stenosis caused by intimal hyperplasia [ 57 ].…”