A critical role of COX-2 in the progression of neointimal formation after wire injury in mice

Abstract

Background: Inflammation plays an important role in neointimal hyperplasia after vascular injury. COX-2 is a key mediator of inflammation and contributes to several inflammatory diseases. Although selective COX-2 inhibitors affect pathological conditions in inflammatory diseases, little is known about the effects on vascular remodeling after mechanical injury. Methods: To clarify the role of COX-2 in vascular remodeling after arterial injury, we made a wire-injury model using C57BL/6J mice. These mice were orally administrated a selective COX-2 inhibitor twice a day. COX-2 mRNA expression was analyzed in injured femoral arteries. Results: COX-2 expression was markedly enhanced in the arterial wall on day 7; the expression was gradually decreased from day 14. In histopathological analyses, the COX-2 inhibitor significantly suppressed the progression of neointimal formation in comparison with non-treated mice. In an in vitro study, RNA was collected from macrophages after stimulation. The stimulation resulted in enhanced expression of IL-6 compared with the control, and the COX-2 inhibitor decreased this expression. Conclusion: COX-2 is enhanced in the neointima after mechanical injury, and inhibition attenuated this. Therefore, regulation of COX-2 may be useful for preventing neointimal formation after coronary intervention.

Inhibition of cyclooxygenase-2 modulates phenotypic switching of vascular smooth muscle cells during increased aortic blood flow

“…Protein expression of COX-2 in the aortic segment was upregulated 1 week after enteric intake (25 mg/kg/day), while the level of cAMP (second messenger of PGI 2 ) in the vasculature was significantly reduced after 3 weeks. Upregulation of COX-2 expression following celecoxib treatment is consistent with the commonly reported compensatory ''switch-on'' response during a chronic deficit of the effective second messenger in the system, such as the enhancement of COX-2 expression on the arterial wall following COX-2 inhibition [15] and over-expression of endothelial nitric oxide synthase (eNOS) when NO is neutralized [16,17]. Furthermore, the decline in cAMP level in the aortic homogenate confirmed that the endogenous COX-2 enzymatic activity in the aortic wall was reduced by pharmacologic inhibition.…”

EP Receptors and Coxibs

“…Involvement of COX-2 and mPGES-1 in these processes has been confirmed by the observation that selective inhibition of both these enzymes results in reduced hyperplasia after vascular injury. 3,8,11 Notably, these findings are in agreement with results from clinical trials in which treatment with selective COX-2 inhibitors reduced neointima proliferation after percutaneous coronary angioplasty and drug-eluting stent placement. 12,13 Nevertheless, despite this beneficial effect on vessel restenosis, no effects (or perhaps an increase 12 in cardiovascular events, ie, myocardial infarction) have been found in these patients.…”

Ibuprofen inhibits migration and proliferation of human coronary artery smooth muscle cells by inducing a differentiated phenotype: role of peroxisome proliferator-activated receptor γ

“…Indeed, one of the main metabolites of arachidonic acid in VSMCs is PGF2α,[37] and this metabolite is a natural selective antagonist of PPARγ [26,27]. Similarly, in‐vivo studies have shown that there is increased expression and activity of COX2 in the intima following vascular injury [17,51]. Furthermore, the synthesis of PGF2α via COX activity is increased by PDGF,[52,53] an important regulator of the differentiation state of VSMCs, which induces dedifferentiation of VSMCs towards a synthetic phenotype and promotes their migration and proliferation [54–56].…”