Cerivastatin-induced apoptosis of human aortic smooth muscle cells through partial inhibition of basal activation of extracellular signal-regulated kinases

Background neficial effects of cerivastatin including hypolipidemic properties have been demonstrated to involve nonlipid as well as lipid mechanisms. In the present study, we examined the mechanisms underlying cerivastatin-induced growth inhibition of human aortic smooth muscle (ASM) cells. s ASM cells were cultured in 96-well plates with or without cerivastatin in the presence or absence of mitogen-activated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase MEK1/MEK 2 inhibitor PD98059. Cell growth was assessed by colorimetric quantitation of NADH, and cell viability was determined by trypan blue dye exclusion method. The induction of apoptosis was determined by propidium iodide (PI) staining method using flow cytometer. The activation of ERKs or c-Jun N-terminal kinases (JNKs) was determined by Western blotting using antibodies (Abs) specific for phospho-ERKs or phospho-JNKs. s ent of the ASM cells with cerivastatin prevented cell growth in a concentration-dependent manner through at least induction of apoptosis. The cerivastatin-induced apoptosis was reversed by coincubation with isoprenoid [mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP)] suggesting a role for isoprenoid in the cerivastatin-induced apoptosis. The cerivastatin cooperated with a MEK1/MEK2 inhibitor PD98059 to induce apoptosis, which appeared to correlate with down-regulation of ERK activation (phospho-ERKs expression) induced by the combination. sion statin-induced blockade of ERK activation in ASM cells might result in growth inhibition including apoptosis, which might explain some aspects of the beneficial effects of cerivastatin on coronary artery disease.