Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-beta and MCP-1.
OBJECTIVE
Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored.


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)-beta1 (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.
Joner
Michael
M
CVPath Institute Inc, Gaithersburg, MD 20878, USA.
Farb
Andrew
A
Cheng
Qi
Q
Finn
Aloke V
AV
Acampado
Eduardo
E
Burke
Allen P
AP
Skorija
Kristi
K
Creighton
Wendy
W
Kolodgie
Frank D
FD
Gold
Herman K
HK
Virmani
Renu
R
D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009924:Organ Culture Techniques; D000077205:Pioglitazone; D011817:Rabbits; D011897:Random Allocation; D015607:Stents; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077205:Pioglitazone