Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-β and MCP-1

Abstract

Objective-Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-␥ agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored. Methods and Results-Hypercholesterolemic New Zealand White rabbits (nϭ45) received bilateral balloon-expandable stents implanted into atherosclerotic iliac arteries. Animals were randomized to oral pioglitazone 3 (low dose) or 10 mg/kg per day (high dose) started on the day of stent implantation; control rabbits received placebo. Tissue harvest was performed 28 days after stenting, and stented segments underwent histology, morphometry, immunostaining for macrophages, and scanning electron microscopy. In selected animals, stented arterial segments were placed in organoid culture for 48 hours, and the conditioned media was assayed for 23 different cytokines. There was a 21% reduction in neointimal area for high-dose pioglitazone treated versus placebo rabbits (PϽ0.005), which was associated with a significant reduction of neointimal macrophages. Analysis of conditioned media revealed an 82% and 74% reduction in the release of monocyte chemoattractant protein-1 (MCP-1) (PϽ0.007) and transforming growth factor (TGF)-␤1 (PϽ0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate genes involved in important cellular functions such as lipid and glucose metabolism. 3,4 Several types of PPARs have been described, including PPAR-␣, PPAR-␥, and PPAR-␦. 5 PPAR-␥ is expressed by endothelial cells, macrophages, mononuclear cells and smooth muscle cells (SMCs) in atherosclerotic plaques. 6,7 PPAR-␥ is known to regulate anti-inflammatory and antiatherogenic responses as well as cell proliferation and migration. 6,7,8,9,10 Thiazolidinediones (TDZs) are insulin sensitizing agents that act as ligands for PPAR-␥. Three TZDs (troglitazone, rosiglitazone, and pioglitazone) have been developed for clinical use in type 2 diabetics. Pioglitazone has been shown to predominantly activate PPAR-␥ and weakly activate PPAR-␣; 11 it is associated with inhibition of carotid intimal thickening in diabetic fatty rats 12 and reduction of coronary restenosis after bare metal stenting in humans. 13 Although a beneficial effect of pioglitazone after stent implantation has been reported before, the mechanism of this favorable outcome remains unknown. Conclusions-OralTo date, this is the first systematic evaluation of TZD effects after deployment of bare metal stents in an atherosclerotic animal model. The aim of this study was to investigate the impact of pioglitazone on neointimal growth after bare MethodsThis study was approved by the Institutional Animal Care and Use Committee of the Armed Forces Institute of Pathology and conformed to the position of the American Heart Association on use of animals in research. Rabbit Model of Experiment...

Effects of PPAR.GAMMA. on hypertension, atherosclerosis, and chronic kidney disease

“…However, numerexpressed dominant-negative PPARγ in endothelium demonstrated the development of endothelial dysfunction in response to a high-fat diet [22]. PPARγ ligands have also been reported to reduce intimal and medial complex thickening in carotid arteries and in-stent restenosis after coronary intervention in both diabetic and non-diabetic patients [23] as well as neointima formation after balloon injury in rats [24] and in-stent restenosis in atherosclerotic rabbits [25]. In order to examine the direct effects of PPARγ ligands on endothelial gene expression, we performed DNA microarray analyses.…”

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

“…142 PPAR␥ agonists reportedly decrease in-stent restenosis in early studies in humans. [143][144][145] The fat-specific PPAR␥-regulated hormone adiponectin may be a target that unites the role of PPAR␥ in adipocytes and TZD effects on inflammation; extensive preclinical data demonstrate that adiponectin exerts antiinflammatory effects and is markedly induced in TZD-treated humans. 139 -141,146 Together, these data provided a rationale for clinical trials examining TZD effects on clinical cardiovascular events in humans (Table 2).…”

Drug-Eluting Stent and Coronary Thrombosis

“…60 Given the importance of tissue factor in the initiation of coagulation and thrombosis, we also proposed dimethyl sulfoxide as a novel coating strategy for DES. 61 Dimethyl sulfoxide prevents vascular smooth muscle cell proliferation and migration, ie, the key mechanisms of restenosis; at the same time, dimethyl sulfoxide inhibits tissue factor upregulation in endothelial cells, vascular smooth muscle, and monocytes and prevents thrombotic occlusion in a mouse carotid injury model.…”