Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice

Neointimal hyperplasia is a critical component of restenosis, a major compl ication of angioplasty and related therapeutic procedures. We studied the e ffects of hyperlipidemia and the nonsteroidal anti-inflammatory drugs, aspi rin (acetyl-salicylic acid; ASA), and sulindac, on neointimal formation in a mouse femoral arterial injury model. At 2 months of age, normolipidemic, wild-type (WT), and hyperlipidemic, apolipoprotein E-deficient (apoE-/-) mi ce were divided into three treatment groups: Western-type diet (WD), WD + A SA (200 mg/kg food), and WD + sulindac (300 mg/kg food). After 1 week, mice underwent arterial injury and treatments were maintained for 4 weeks. Hist omorphometry of the injured arteries showed striking effects of plasma chol esterol levels and drug treatment on neointimal hyperplasia. In the WD or W D + ASA groups, apoE-/- mice had twice the neointimal area than WT mice (ap proximate to 30,000 vs. 13,000 mum(2) per section; P < 0.0001). Compared wi th ASA or WD alone, sulindac treatment resulted in <approximate to>-70% (P = 0.0001) and 50% (P = 0.01) reductions in the neointimal area in apoE-/- a nd WT mice, respectively. ASA, at a dose sufficient to inhibit platelet agg regation, did not affect neointimal formation in mice of either genotype, E vidence of macrophages was noted in the lesions of apoE-/- mice in the WD a nd WD + ASA groups, but remarkably, none was detectable with sulindac treat ment, despite hyperlipidemia. suggesting early steps in the response to inj ury were abrogated. These results demonstrate sulindac reduces neointimal f ormation in both normolipidemic and hyperlipidemic settings and raise the p ossibility that similar benefits may be obtained in patients undergoing ang ioplasty and related procedures.