γ-Tocopherol, but not α-tocopherol, potently inhibits neointimal formation induced by vascular injury in insulin resistant rats

Insulin resistance may enhance the neointima formation via increased oxidative stress. However, clinical trials investigating the benefit of antioxidant therapy with α-tocopherol showed negative results. Recent studies showed that chemical characteristics of γ-tocopherol are distinct from those of α-tocopherol. We hypothesized that γ-tocopherol is superior to α-tocopherol in preventing the neointima growth after arterial injury in insulin resistance. Male rats were fed with standard chow or a high fructose diet for induction of insulin resistance. Thereafter, the left carotid artery was injured with a balloon catheter. After 2 weeks, the carotid arteries were harvested and histomorphometrically analyzed. The neointima-media ratio of the injured artery was significantly greater in insulin resistance group (n = 8, 1.33 ± 0.12) than in normal group (n = 10, 0.76 ± 0.11, p < 0.01). γ-Tocopherol (100 mg/kg/day) reduced the ratio (n = 5, 0.55 ± 0.21, p < 0.01 vs. insulin resistance group), while α-tocopherol was without effect (n = 7, 1.08 ± 0.14). The quantification of plasma phosphatidylcholine hydroperoxide, an indicator of systemic oxidative stress, and dihydroethidium fluorescence staining of the carotid artery, an indicator of the local superoxide production, showed that oxidative stress in the systemic circulation and local arterial tissue was increased in insulin resistance. Both tocopherols decreased plasma phosphatidylcholine hydroperoxide, but failed to suppress the superoxide production in the carotid arteries. Increased 3-nitrotyrosine in neointima by insulin resistance was greatly reduced only by γ-tocopherol. In conclusion, γ-tocopherol, but not α-tocopherol, reduces the neointima proliferation in insulin resistance, independently of its effects on superoxide production. The beneficial effect may be related with its inhibitory effects on nitrosative stress.