Naringenin Inhibits Neointimal Hyperplasia Following Arterial Reconstruction With Interpositional Vein Graft

Vessels respond to injury by a healing process that includes the development of neointima. Stenosis secondary to neointima formation is the main cause of failure following arterial reconstructions, Vessel wall homeostasis is regulated by proinflammatory cytokines that affect smooth muscle cell proliferation, growth, migration, and death. We assessed the hypothesis that naringenin, a flavinoid possessing anti-inflammatory, antioxidant, and antiproliferative activities, reduces neointimal hyperplasia (NIH) following vascular injury. Arterial injury was created by interposition grafting of autologous right superficial epigastric vein graft into the right femoral artery (FA) in 48 male Sprague-Dawley rats. Following injury, the rats were divided into 4 groups (n = 12). Two groups were treated with naringenin (100 mg/kg intraperitoreal q daily) for 2 and 4 weeks each while 2 control groups received normal saline for the same durations. For Sham group In = 10), the FA and vein were isolated without any additional procedure. Rats were killed at the end of treatment regimen in all groups, and FAs were harvested. Thickness of intima was measured in histologic sections, and levels of platelet derived growth factor (PDGF)-BB, TNF alpha, and Ki67 labeling index (Ki67 L1) were quantified in immunohistochemical analyses to assess the amount of NIH and mechanisms underlying its formation. Although there was no significant difference between the groups at 2 weeks, neointima thickness was lower in the naringenin treated group at 4 weeks (23.7 +/- 2.3 vs. 35.6 +/- 2.6 mu m in control group; P < 0.001). The levels of PDGF-BB, and TNF alpha were lower in naringenin treated groups at both 2 weeks (PDGF-BB [0.21% +/- 0.03% versus 0.39% +/- 0.05% in control group, P < 0.001), TNF alpha (21.2% +/- 0.8% vs. 36.1% +/- 1.9% in control group, P < 0.001]) and 4 weeks (PDGF-BB [0.25% +/- 0.03% vs. 0.57% +/- 0.09% in control group, P < 0.001], TNF alpha [25.5% +/- 1.8% vs. 45.0% +/- 2.9% in control group, P < 0.001]). Ki67 L1 was lower in naringenin treated groups at 2 weeks (13.9% +/- 2.8% vs. 18.7% +/- 3.7% in control group, P < 0.05), and at 4 weeks (17.5% +/- 2.6% vs. 31.1% +/- 4.7% in control group, P < 0.001), indicating a lower level of cellular proliferation. Naringenin reduces NIH following arterial reconstruction. This may be mediated by a decrease in PDGF-BB and TNF alpha levels and the resulting down-regulation of smooth muscle cells' migration and proliferation.