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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:182.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Michael Joner; Andrew Farb; Qi Cheng; Aloke V. Finn; Eduardo Acampado; Allen P. Burke; Kristi Skorija; Wendy Creighton; Frank D. Kolodgie; Herman K. Gold; Renu Virmani

From CVPath Institute Inc (M.J., Q.C., F.D.K., E.A., A.P.B., W.C., K.S., R.V.), Gaithersburg, Md; the Center for Devices and Radiological Health, U.S. Food and Drug Administration (A.F.), Rockville, Md; Cardiac Unit (A.V.F., H.K.G.), Department of Internal Medicine, Massachusetts General Hospital, Boston, Mass.

Correspondence to Renu Virmani, MD, Medical Director, CVPath, International Registry of Pathology, 19 Firstfield, Road, Gaithersburg, MD 20878. E-mail rvirmani{at}cvpath.org

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 (n=45) 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 (P<0.005), 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) (P<0.007) and transforming growth factor (TGF)-ß1 (P<0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo.

Conclusions— Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.

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 have not been explored. Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.

Key Words: inflammation • pioglitazone • rabbit • restenosis • stent

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