Antioxidants Suppress Plasma Levels of Lectinlike Oxidized Low-Density Lipoprotein Receptor-Ligands and Reduce Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits

Abstract

We examined effects of a physiologic concentration of pitavastatin (0.01 μmol/L) on oxidant-induced apoptosis in cultured human vascular smooth muscle cells (VSMCs). Apoptosis was induced in VSMCs by hydrogen peroxide (H₂O₂, 300 μmol/L), as evidenced by in situ nick end-labeling and scanning electron microscopy. This apoptotic response was accompanied by increased activation of mitogen-activated protein kinases (MAPKs-ie, increases in the phosphorylated forms of extracellular signal-regulated kinase (p-ERK), c-Jun N-terminal kinase (p-JNK), and p38 MAPK (p-p38 MAPK). Although pitavastatin alone did not induce VSMC death, pretreatment with pitavastatin significantly enhanced H₂O₂-induced apoptosis and prolonged activation of JNK and p38 MAPK (for up to 24 h) but not ERK. Expression of MAPK phosphatase-1 (MKP-1) also was upregulated by H₂O₂, but this was not affected by pitavastatin. The apoptosis accelerating effect was observed also in simvastatin but not in pravastatin. Treating VSMCs with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate completely blocked the statin-induced enhancement of VSMC apoptosis, suggesting that protein prenylation is critically involved. It thus appears that pitavastatin enhances H₂O₂-induced VSMC apoptosis, at least in part, via increases in MAPK activation and protein prenylation, but independently of MKP-1 expression, which consequently results in reduction of VSMC population.