Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, Decreases Monocyte Chemoattractant Protein-1 Expression and Neointimal Hyperplasia in the Rabbit Atherosclerotic Balloon Injury Model

Abstract

The inflammation in response to vascular injury is becoming increasingly recognized as a potential contributor to restenosis. Cyclooxygenase-2 (COX-2) is the inducible form of cyclooxygenase and has been shown to be involved in the proinflammatory response of vascular tissue. Bilateral femoral artery lesions were induced by air desiccation in New Zealand White rabbits followed by high cholesterol diet feeding for 28 days. Balloon injury and stent implantation were performed at the preinjured vessel segments. Immunostaining showed that uninjured vessel segments stained positive only for COX-1 but not for COX-2. Injured vessel segments showed, in addition to COX-1, significant positive staining for COX-2. In the efficacy study, celecoxib (75 mg/kg/d) was administered orally beginning 3 hours before balloon injury or stent implantation on day 28 and daily for 21 days. Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 and -9 (MMPs) expression were quantified in arterial extracts 4 days after balloon injury by Western blot and gelatin zymography. Morphometric analysis and immunostaining for macrophages were performed 21 days after balloon injury. Celecoxib treatment significantly decreased MCP-1 expression (P < 0.01). Neointimal hyperplasia was significantly inhibited by celecoxib in both balloon injury and stent models (0.49 +/- 0.20 versus 0.70 +/- 0.35 mm2 from balloon injury model, P < 0.05, and 0.81 +/- 0.25 versus 1.69 +/- 0.43 mm2 from stent model, P < 0.05), accompanied by reduced macrophage infiltration. We conclude that celecoxib decreases the inflammatory response and intimal hyperplasia following vascular injury, possibly through inhibition of MCP-1 expression, implying a pivotal role of inflammation in the pathogenesis of restenosis.