Restenosis Revisited

P. A. Calvert, M. R. Bennett
2009 Circulation Research  
D espite the advent of drug-eluting stents, restenosis, in-stent stenosis (ISS), and the consequences of delayed healing after drug eluting stents (DES) are still a cause for concern and represent a significant disease burden. 1-4 ISS is predominantly caused by neointima formation, which is itself caused by the cumulative effects of vascular smooth muscle cell (VSMC) proliferation, migration, deposition of extracellular matrix, and reorganization of thrombus after stenting. 5 Cell proliferation
more » ... after stenting occurs both early, as part of the acute injury response, and late, located around stent struts, in part, as a foreign body reaction. 5 Whereas some neointima formation is necessary for vessel healing after stenting, to bury the stent struts within the vessel wall and to prevent exposure to the flowing blood, excessive neointima formation renarrows the lumen. Even though many processes are involved in ISS, the greatest therapeutic success has come from antiproliferative agents, the most advanced and accepted of which are sirolimus (rapamycin) and paclitaxel. Both rapamycin-and paclitaxel-eluting stents have significantly reduced the incidence of ISS, with ISS rates of 3.2% at 240 days for rapamycin-eluting stents 6 and 5.5% at 270 days in paclitaxel-eluting stents. 7 These impressive results have translated into the widespread use of DES. However, there are problems associated with DES use, among which is late stent thrombosis (LST). LST is caused by delayed endothelialization and delayed intimal/medial healing, resulting from the potent antiproliferative action of the drugs. 8 Indeed, the best histological predictor of LST is endothelial coverage, and the best morphometric predictor of LST is the ratio of uncovered to total stent struts. 9 Importantly, neither rapamycin nor paclitaxel are specific for VSMCs, particularly those present in the primary plaque or the ISS lesion, and both drugs have a marked dose-dependent effect, an important consideration when the stent acts as a local drug reservoir. Indeed, heterogeneity of healing is common in DES with evidence of LST, 9 with insufficient neointima for strut coverage, ongoing inflammation, failure of stent apposition, and thrombus formation. 10 This lack of specificity, with the resulting failure of healing, has spurred the development of newer agents, polymers, and stent coverings that continue to inhibit proliferation, migration, inflammation, matrix synthesis/deposition, or combinations of these processes but may not have the same effects on endothelial cells. It is against this backdrop that the study by Kim et al 11 in this issue of Circulation Research will provoke interest. ␤-Lapachone (␤L) (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2b]pyran-5,6-dione) is a potent antitumor agent that stimulates NAD(P)H:quinone oxidoreductase (NQO)1 activity. ␤L dose-dependently inhibited neointimal formation induced by balloon injury in the rat carotid artery model, and serum-or platelet-derived growth factor-induced VSMC proliferation in culture, by inhibiting G 1 /S phase transition. The final common pathway appeared to be activation of the tumor suppressor gene p53, downregulation of cyclins D and E, and upregulation of the cyclin-dependent kinase inhibitor p21, with the subsequent reduction in phosphorylation of the retinoblastoma gene product (pRB) and G 1 arrest. Inhibition of proliferation via pRB hypophosphorylation is used by numerous other antiproliferative agents that inhibit VSMC proliferation in vitro and/or in vivo. However, what is different in the article by Kim et al 11 is the detailed dissection of the upstream mechanism of action of ␤L. In rat and human VSMCs, ␤L increased the phosphorylation of AMP-activated protein kinase (AMPK), a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. AMPK activation has been shown previously to cause cell cycle arrest in human and rabbit VSMCs, via the same mechanism, 12 and the AMPK activator AICAR inhibits both angiotensin II-induced VSMC proliferation and neointimal formation in rat balloon-injured femoral arteries. 13 The mechanism of arrest associated with AMPK activation is also p53 upregulation and phosphorylation and increased expression of p21. 13 In addition, AMPK activation phosphorylates and inactivates a number of metabolic enzymes that mediate ATP-consuming cellular events, including ACC1 (acetyl-coenzyme A carboxylase 1). In the present study, ␤L increased the phosphorylation of ACC1, and the effect of ␤L required AMPK, because AMPK chemical inhibitors or a dominant-negative blocked the ␤L-induced suppression of cell proliferation and the G 1 arrest, in vitro and in vivo. Mammals express at least 2 AMPK upstream kinases, including LKB1, the serine/threonine kinase inactivated in the Peutz-Jeghers familial cancer syndrome (which is activated by an increase in AMP/ATP ratio) and Ca 2ϩ /calmodulin-dependent kinase kinase (CaMKK)␤ (which is activated by cellular Ca 2ϩ concentration). In addition, NQO1 is a cytosolic antioxidant flavoprotein that catalyzes the reduction
doi:10.1161/circresaha.109.196345 pmid:19359603 fatcat:cba4pdkc7nb2jhvbugi3fmffga