tatins reduce the serum cholesterol level by inhibiting 3-hydroxyl-3-methyl coenzyme A (HMG-CoA) reductase. Mega-trials have demonstrated the safety and efficiency of long-term cholesterol-lowering therapy using low-dose statin, 1 and that intervention with statins prevent cardio-and cerebrovascular events in patients with hypercholesterolemia. [2][3][4][5][6] It has been suggested that the preventive effect of statins is attributable to their cholesterol-lowering action, but there is research demonstrating that statin therapy also prevents cardiovascular events in patients with an average cholesterol level, 4 suggesting that statins prevent coronary vascular events not only through cholesterol-lowering but also through some other process. The mechanisms of these effects beyond the reduction of cholesterol, the so-called pleiotropic functions, have been gradually elucidated by a number of studies.The pleiotropic functions of statins are involved in the regulation of cell adhesion molecules and the cell cycle, 7-11 inhibition of cell growth and/or induction of apoptosis in vascular smooth muscle cells, [12][13][14] 16,17 and inhibition of vascular NAD(P)H oxidase, 18 among others. Moreover, we have reported that in experiments in dogs cerivastatin inhibited migration of ECs in vitro and intimal thickening of balloon-injured arteries in vivo. 19 With respect to angiogenesis, some researchers have show that simvastatin and cerivastatin promote collateral vessel formation in ischemic tissues of animal models. 20,21 On the other hand, these same drugs reportedly inhibited the migration and viability of ECs, and interrupted angiogenesis. [22][23][24] More recent reports indicate that simvastatin, cerivastatin and atorvastatin exert a biphasic effect on cultured ECs and angiogenesis in a dose-dependent manner. [25][26][27] "New generation" statins, which have a stronger effect on cholesterol reduction than conventional statins, have been developed and one of them, pitavastatin, exhibits a potent hypolipidemic effect in both animal and human trials. [28][29][30] At a dose of 4 mg/day pitavastatin has been shown to be equivalent to atorvastatin at a dose of 80 mg/day in reducing low-density lipoprotein in heterozygous familial hypercholesterolemia patients. 29 There are some reports of its pleiotropic effects on ECs; pitavastatin increased thrombomodulin, tissue-type plasminogen activator and nitric oxide production, and decreased plasminogen activator inhibitor 1 and inflammatory cytokine. [31][32][33][34] Moreover, pitavastatin has augmented capillary formation in the ischemic limb of an animal model. 35 These pleiotropic effects of pitavastatin are similar to those of conventional statins and so it is interesting to know whether or not the effect of pitavastatin on the migration, proliferation, and
Methods and ResultsThe effects of pitavastatin on the migration, proliferation and viability of human epidermal microvessel endothelial cells (HMVECs) were examined using scratch assay, chemotaxis chamber, bromodeoxyuridin...
